TWI313683B - Novel vinylogous acids derivatives - Google Patents

Description

1313683 IX. DESCRIPTION OF THE INVENTION: SUMMARY OF THE INVENTION The present invention relates to novel enodic acid derivatives of formula (I):

(I) wherein: A is -CH2-, -Ο- or -NR'-, wherein R' is hydrogen or C..6 alkyl, or R' and R4 form C2.5 alkyl; R1 is hydrogen, Halogen, nitro, cyano, amine, Cw alkyl, heteroalkyl, C3.7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, thiol, Ci-6 alkoxy, -NR 'R", -(C0.6 alkyl)-NR'R, wherein R· and R" are independently selected from the group consisting of wind, Ci_6 alkyl, heteroalkyl, carbaryl, C].6 alkylcarbonyl , optionally substituted C3-7 cycloalkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heterocyclylcarbonyl, Cm alkylsulfonyl, Optionally substituted C3-7 cycloalkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl and optionally substituted heterocyclylsulfonyl a group, or -(c0_6alkylene)-〇R' 'wherein R· is hydrogen, Ci-6 alkyl, heteroalkane 116339.doc 1313683, fluorenyl or C..6 alkylcarbonyl; R2 R2 and R2 are independently hydrogen, halogen, cyano, nitro, amine, amine substituted by mono or diCi6 alkyl, Cu graft C2·6 alkenyl, C 2_6 alkynyl, heteroalkyl, hydroxy or hydrazine "alkoxy; r3 is hydrogen, halogen, cyano, nitro, amine, substituted by mono or di c!-6 alkoxy Amino, Cw alkyl, C2-6 alkenyl, C2·6 alkynyl, hetero-alkyl, hydroxy, Cw alkoxy, optionally substituted c3-7 cycloalkanyl, optionally substituted aryl, Optionally substituted heteroaryl 'optionally substituted heterocyclic group, optionally substituted C3.7 cycline-C!·6 alkyl, optionally substituted aryl _cN6 alkyl, 视a substituted heteroaryl 弋 16 alkyl group or an optionally substituted heterocyclic group - Cw alkyl group; R 4 is hydrogen 'halogen' cyano group, nitro group, amine group, substituted by mono or bis-6 alkyl group Amino group, Cm alkyl group, C2·6 alkenyl group, C2·6 alkynyl group, heteroalkyl group, hydroxy group, C,·6 alkoxy group, optionally substituted c3 7 cycloalkane group, optionally substituted Aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted c3_7 cycloalkyl-Cw alkyl, optionally substituted aryl hydrazine "alkyl, optionally Substituted heteroaryl _c16 alkyl or, as appropriate And a heterocyclic group-Cw alkyl group; R5 is hydrogen or c]_6 alkyl group; or R4 and H5 together with the carbon eyebrow to which it is attached, and the ι± atom constitute an optionally substituted C3-7 cycloalkyl ring. Or optionally substituted heterocyclyl ring; R6 is hydrogen or c!_6 alkyl; 116339.doc 1313683 and its prodrugs and pharmaceutically acceptable salts. Furthermore, the present invention relates to the use of Methods of Compounds and Membranes: Pharmaceutical preparations containing such compounds, uses of such compounds for the preparation of pharmaceutical preparations, and a method for making the intermediates. The compound of formula (1) inhibits chymosin. The chymosin is a serine acid protease whose expression pattern is completely limited to the subpopulation of mast cells (MCT hypertrophic cells). The chymosin is activated only after mast cell activation and degranulation, which limits the enzyme activity to MCT positive tissue. The chymosin specifically decomposes many pathologically relevant matrices (Raymond, W. W., SW RUggles et al; JBC 2003 278(36): 34517-34524), whereby it activates angiotensin, endothelin, TGFb, 111, SCF, collagenase and degradation proteins such as thrombin, FN, APO Al, APO A2. This mode makes chymosin an attractive tap for allergic, inflammatory and fibrotic diseases. In fact, many successful animal studies on chymosin inhibitors have been shown to be effective in allergic > animals, vascular injury and atherosclerosis (D〇ggreU S A,

Wanstall JC Can J Physiol Pharmacol. February 2005, 83(2): 123-30 ; Lindstedt KA, Kovanen PT. Curr Opin

Lipidol. October 2004, 15(5): 567_73; Reed CE, Kita H. J Allergy Clin Immunol. November 2004, 114(5): 997-1008;

Takai S et al., Eur J Pharmacol. October 6, 2004, 501(1-3): 1-8; Takai S et al., Trends Pharmacol Sci. October 2004, 25(10): 5 18-22 Takai S, Miyazaki M. Curr Vase Pharmacol· June 2003, 1 (2): 21 7-24). 116339.doc -8- 1313683 Therefore 'inhibiting chymosin in allergies, asthma, peripheral arterial obstructive disease' severe limb ischemia, vulnerable atherosclerotic plaque, unstable angina, congestive heart failure, left ventricle Hypertrophy, ischemia_reperfusion injury, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel disease, Crons disease, wound healing (surgery/diabetes ulcer/CLI ) appears as a useful therapy. The present invention provides a novel compound of formula (I) which is a chymosin inhibitor.

Unless otherwise stated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms of the invention. The term "or," or "dentate group" means fluorine, chlorine, bromine and iodine (group), of which fluorine or gas (base) is preferred. The term ''C, ·6 alkyl", alone or in combination with other groups, means a branched or straight-chain monovalent alkyl group having from 1 to 6 carbon atoms. The term is further exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl-Cw alkyl. The earth is alive "heteroalkyl", and the substituents are independently selected from the group consisting of nitro, hydroxy, dentate, cyano, C alkoxy, carbaryl, and C yl. a group consisting of a base 1, a Ci 6 — , a c alkyl group, a (3, .6 alkyl group, an amine group, and an amine group substituted by a mono or a di c. The term is _ / 2 a / It is exemplified by the following groups: 2-hydroxyethyl, hydrazine, _ 丞 氟 fluoromethyl substituted by 1 hydroxy or 1 to 3 phases or different halogen atoms c] _ 6 alkyl Preferably, the term & ring base ", alone or in combination with other groups, means a saturated monovalent cycloalkyl group of 3 to 7 ring carbons, for example, cyclopropyl, ring 116339.doc 1313683, Cyclohexyl. C. 6 alkoxy, alone or in combination with other groups, means R|-0- group 'where R| is Cl_6 alkyl. · Terminology "C2.6 alkenyl , alone or in combination with other groups, means a straight or branched hydrocarbon residue comprising an olefinic bond having 2 to 6 rice atoms, such as, vinyl, 2, propenyl. ", either alone or with other groups ", meaning that it has a linear or branched hydrocarbon residue containing two bonds of 2 to 6 carbon atoms, il /, ethynyl, 2-propynyl. "浯CG.6 alkyl" a single bond or a linear or branched divalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. Cg stretch alkyl means a bond. - The term "aryl", alone or in combination with other groups , meaning phenyl or naphthyl, preferably phenyl. The heterocyclic group, alone or in combination with other groups, means a non-aromatic mono or bicyclic group having 3 to 8 ring atoms, 1 or 2 ring atoms of the towel are heteroatoms selected from N 〇 or 8 (〇) 11 (where n is an integer from 〇 to 2), and the remaining ring atoms are C. The term "杂杂其丨"咅) θ 丞 ming has a monocyclic or bicyclic group having 5 to 12 ring atoms having at least one aromatic ring containing fluorene, 2 or 3 selected from N, fluorene and % heteroatoms, and the remaining ring atoms are fluorene. Preferably, the point of attachment of the heteroaryl group will be attached to the aromatic ring. The substituted aryl group, as the case may be substituted, the heteroaryl group which is substituted according to the condition, and the substituted heterocyclic group" Condition replaced C3-7 ring 'Knife' 5 gastrointestinal conditions are selected from one or more independently selected from the group consisting of halogen, nitrate 116339.doc -10- 1313683, cyano, amine, Cw alkyl, c2.6 alkenyl, c2_6 alkyne An aryl group, a heteroaryl group, a heterocyclic group and a C3 group substituted with a substituent of a group consisting of a group consisting of a group of a hydroxyl group, a C?-6 alkoxy group, a mono- or a di-alkyl-substituted amino group and a heteroalkyl group; 7-Cycloalkyl. Preferred groups of the chemical groups defined above are those specifically exemplified in the examples.

The compound of formula (I) forms a pharmaceutically acceptable acid addition salt. Examples of such pharmaceutically acceptable salts are those formed from a compound of formula (1) with a physiologically compatible inorganic acid such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with an organic acid such as methanesulfonic acid. A salt formed of p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salts" refers to such salts. The compound of the formula (1) in which the C00H group is present can further form a salt. Examples of such salts are metal salts, soil metal salts and ammonium salts such as 'Na, κ, Ca and trimethylammonium salts. The term "medical acceptable salt" also refers to such salts. The acid addition salt as described above, or, as the case may be, means that the event or condition described later may be, and the brother and the plug may not necessarily occur 'and the description includes an event or condition. The month/and the event or condition* occurred in the case of Fangmei, the sound of the gods, the condition of the burning, including the fang: the presence of 'but not necessarily, and the shape. Substituted by the appearance of the base and the aryl group without the (four) substitution of the pharmaceutically acceptable excipient " sound into the 榀β " species suitable for the preparation of II shovel red and usually safe, toxic, The table is ready for business, and it is neither bio-cutting nor defective. 116339.doc 1313683 In addition, the undesirable excipients are used for the purpose of medicine. It can be used as a veterinary material and as a remedy for human medicine. In the "medical hurricane h - 曰次甲" monthly patent dry circumference used in this manual. The wind office d includes one or more of the shape two === bond characteristics or order or its atomic * between rows It is called "isomer". Its atom is in the mirror: the isomeric system is called "stereoisomer". Not for each other =: stereoisomeric system is called "diastereomer" ", and those who mirror each other's A are called, enantiomers, .. If the two groups of nickname centers, for example, if a carbon atom and four not two = The second may have a pair of enantiomers. The enantiomer may be characterized by its absolute configuration of the % center and described by the R and S order rules of Cahn, lng01d log, or by Where the molecule rotates the plane of the polarized light (4) and is named as the right-handed or left-handed (ie, (+) or (I)-isomer respectively). The palm compound can be individual enantiomers. Or in the presence of a mixture thereof. A mixture containing equal proportions of enantiomers is referred to as an externally-rotating mixture " The compound of (I) may have one or more asymmetric centers. Unless otherwise stated, the description or nomenclature of a particular compound in the specification and claims is intended to include individual enantiomers and mixtures thereof (external elimination). Spiral or other) as well as individual epimers and mixtures thereof. Methods for determining stereochemistry and isolating stereoisomers are well known in the art (see "Advanced Organic Chemistry", 4th edition, J March, John Wiley, and Sons, New York, 1992, pp. 116339.doc -12-1313683.) Although the broadest definition of the invention has been described above, certain equations (1) The compound is preferred. l) A preferred compound of the invention is a compound of formula (I) wherein: Rule 3 is C]-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl An optionally substituted aryl 1-6 alkyl or an optionally substituted heteroaryl cN6 alkyl. ii) Another preferred compound of the invention is a compound of formula (I) wherein: R is C! _6 alkyl, phenyl C!·6 alkyl; a phenyl group substituted with 3 fluorine atoms; or a heteroaryl group substituted by 3 fluorine atoms, wherein the heteroaryl group is a monocyclic aryl group having 5 or 6 ring atoms, which contains 1 or 2 ring nitrogen atoms or 1 ring sulfur atom. m) Another preferred compound of the invention is a compound of formula (1) wherein: R3 is phenyl. iv) Another preferred compound of the invention is A compound of formula (I), wherein: R is C!-6 alkyl, _((0〇.6) hNR'R, wherein R1 and R" are independently selected from hydrogen, C1_6 alkylcarbonyl, optionally Substituted aromatic earth Ik group, optionally substituted hydroxy group, optionally substituted aryl sulfonyl group and optionally substituted heteroaryl sulfonyl group; or alkyl group) - 〇R, wherein R is hydrogen or €16 alkylcarbonyl. V) Another preferred compound of the invention is a compound of formula (I), in 116339.doc 1313683: R is 匸 "alkyl; -(C2-6 extendable)-NR'R", wherein R' And R" are independently selected from the group consisting of hydrogen, ethyl fluorenyl, arylcarbonyl (wherein the aryl group is optionally substituted with 1 or 2 perfluorodecyl groups) and an arylsulfonyl group; or - (C2·6 stretch Alkyl)-0R' 'wherein R' is hydrogen or acetyl.

Vl) Another preferred compound of the invention is a compound of formula (I) wherein: R1 is 2-aminoethyl, 2-ethylamidoethyl, 2-ethylamino-2,2-di Methyl ethyl, methyl, isopropyl or 2-hydroxyethyl. Vii) Another preferred compound of the invention is a compound of formula (1) wherein: 'R2, r2, and R2" are independently hydrogen, dentate, C丨·6 alkyl or CK6 alkane group 0, which is halogenated thereof viii) Another preferred compound of the invention is a compound of formula (1):

Two of R2, R2, and R2> are hydrogen, and the other is hydrogen, Cw alkyl or c _6 methoxy. Ix) Another preferred compound of the invention is also a/T, Λ u σ in the compound of formula (I): X) two of R2, R2' and R2" are hydrogen, fluoro, fluoro, hydrazine The base, ethyl or oxime is another preferred compound of the invention &: and the other is a hydroquinone compound of formula (1) which is chlorine and the other is attached. Two of R2, R2' and R2" are at the 5 or 6 position of hydrogen 116339.doc -14-1313683 and are selected from the group consisting of hydrogen and chlorine. Another preferred compound of the invention is a compound of formula (1) wherein R6 is hydrogen. Another preferred compound of the invention is a compound of formula (1) wherein: R4 is hydrogen 'Cw alkyl, optionally substituted C37 cycloalkyl', optionally substituted aryl, optionally substituted C" a 5-alkyl heart-burning group or an optionally substituted aryl Ci 6 alkyl group, and R 5 is hydrogen or a C 6 .6 alkyl group; or R and R and the attached (four) sub-member thereof constitute an optionally substituted C 3 -7 ring-burning base ring. Preferred compounds of the invention m are compounds of formula (1) wherein A is -CH2-. Another preferred compound of the invention is a compound of formula (1) wherein: A is -CH2-'phenyl and R5 is hydrogen. Another preferred embodiment of the invention is a compound of formula (I) wherein _A is -NR1-, and φp is such that R is 氲 or Ck6 alkyl. Another preferred compound of the invention is a compound of the formula (1) in which: A is -NR, - (wherein R is a gas VIII > methine), R4 is isopropyl and R is hydrogen. Xvii) Another preferred embodiment of the invention A is -〇-. Xviii) Another early sputum of the present invention is a compound of the formula (1), a fluoro group, a fluorenyl group and a bis) xii) xiii) xiv) XV) xvi) a compound of the formula (I), 116339.doc 15 1313683 wherein: A is a substituted C3·7 % alkyl c 。 6 alkyl or an optionally substituted aryl C 6 6 alkyl, and R 5 is hydrogen or Ci·6 alkyl; or R and R The attached carbon atom - which constitutes a C3_7 ring-burning ring which is optionally substituted. Xix) Another preferred compound of the invention is a compound of formula (1) wherein .A is -O-'R is phenyl, phenylhydrazine, isobutyl, cyclohexylethyl or phenethyl and R5 is hydrogen or methyl. XX) Another preferred compound of the invention is a compound of formula (1) wherein: R3 is C,6 alkyl, optionally substituted aryl 'optionally substituted heteroaryl, optionally substituted a 6-alkyl group or an optionally substituted heteroaryl Cw alkyl group, preferably 113 is a (:1-6 alkyl group, optionally substituted by 1 to 3 fluorine atoms, optionally 1 to 3 a heteroaryl group substituted by a fluorine atom (wherein the heteroaryl group is a monocyclic aryl group having 5 or more ring atoms which contains 1 or 2 ring nitrogen atoms) or a phenyl CN6 alkyl group, particularly a phenyl group; R1 Is C. .6 alkyl, -(c0-6alkyl)-NR'R" (wherein R' and R" are independently selected from hydrogen, C!-6 alkylcarbonyl, optionally substituted arylcarbonyl, Optionally substituted heteroarylcarbonyl, optionally substituted arylsulfonyl and optionally substituted heteroarylsulfonyl group) or -(C«)-6 extended alkyl)-〇R (wherein R is hydrogen or Cl_6 alkylcarbonyl) 'Preferably, R1 is C, -6 alkyl, -(C2_6 alkylene)-NR'R" (wherein the ruler and ruler are independently selected from Hydrogen, ethyl sulfonyl, aryl] I633 9.doc • 16· 1313683 Rebel (where the aryl group is substituted by 1 or 2 perfluoromethyl groups) and the aryl group consisting of fluorenyl groups) or _(C2 6 stretching base)_QR' (where ^ Is chloro or ethoxylated) 'Specially 2-aminoethyl, 2-ethylamidoethyl, acetamido-2,2-dimethylethyl, methyl, isopropyl or 2_ Hydroxyethyl; R, R and R2 are independently hydrogen, halogen, Ci 6 alkyl or Cu alkoxy, preferably two of R2, R2. and R2" are hydrogen and the other is hydrogen, halogen , Ci_6 alkyl or Ci0 alkoxy, more preferably, two of R and R are hydrogen, and the other is hydrogen, chloro, fluoro, methyl, ethyl or methoxy, in particular, Two of R2, R and R are hydrogen, and the other is at the 5 or 6 position of the anthracene ring and is selected from the group consisting of hydrogen 'a gas group, a fluorine group, a methyl group and an ethyl group; R6 is hydrogen R is hydrogen, c]-6 alkyl, optionally substituted c3 7 cycloalkyl, optionally substituted aryl, optionally substituted C3 7 cycloalkyl 6 alkyl or, as appropriate, substituted Alkyl C丨-6 alkyl; R5 is hydrogen or CN6 alkyl; or R4 and R5 are attached to the carbon atom to which they are attached A C3-7 cycloalkyl ring which is optionally substituted. xxi) A preferred compound of group XX) is a compound of formula (1) wherein: A is -CH2-. If A is -CH2-, preferably, R4 is phenyl and R5 is hydrogen. xxii) Another preferred compound of group XX) is a compound of formula (1), which is 116339.doc -17- 1313683: A is -NR,-, wherein R is hydrogen or ^ A. If A is -NR, -, wherein R is hydrogen or methyl R4 is isopropyl and R5 is hydrogen. Another preferred compound of the oxime group XX) is a compound of the formula (1) wherein: A is -0-. Preferably, if A is, r4 is hydrogen, phenyl, ci 6 alkyl, optionally substituted C3.7 cycloalkyl Ck6 alkyl or, as appropriate

The substituted aryl group and R5 is hydrogen or C"alkyl; or R^R5 and the carbonaceous material to which it is attached constitute a C3-7 cycloalkyl ring which is optionally substituted. More preferably, if A is, R4 is phenyl, benzyl, isobutyl, 2-cyclohexylethyl or phenethyl, and r5 is hydrogen or methyl. Another preferred compound of the invention is a compound of formula (1) wherein: A is -CH2-, -〇- or torn ... wherein R is hydrogen or cw alkyl

Preferably, hydrogen or hydrazine is preferably xxiv) xxv) Another preferred compound of the invention is a compound of formula (1) wherein: hydrazine is -NR, -' wherein R, and hydrazine constitute a hydrazine alkyl group . Nvi) Another preferred compound of the invention is a compound of formula (1) which is 3-[(5-fluoro-3-methylphenyl-indenyl)4,yl-5-isopropyl-1,5- Dihydro-pyrrole-2-g, 3-[(5-fluoro-3-indolyl-1H-indol-2-yl)-phenyl-methyl]4-hydroxy-5~isopropyl- 1-mercapto-I,5-dihydro-pyrrol-2-one, 4-hydroxy-5-isopropyl-3-[(3-indolyl-1H_吲哚_2_yl)-phenyl-methyl 1,1,5-dihydro-D-pyrrol-2-one, 116339.doc -18· 1313683 3·[(5-murine-3-isopropyl-1Η-σ引.多-2·基Phenyl-fluorenyl]-4-ylamino-5 isopropyl-1,5-diox-sigma ratio -2, @同, Ν-(2-{2·[(5-benzyl) 4--4-yl-2-oxo-2,5-dimurfenan-3-yl)-phenyl-indenyl]_6-murine-1Η·σ bow|p-3-yl}B Ethylamine, 5-benzylamine-3·{[6-fluoro-3-(2.hydroxyethyl)-1Η-indol-2-yl]-phenyl-indenyl}- 4-hydroxy-5-furfuran-2-one, 3-{[3-(2-amino-ethyl)-6-ranyl 0-2-yl]-phenyl-fluorenyl}-5·benzene Mercapto-4-hydroxy-5indole-furan-2-one; salt formed with acetic acid, 5-benzyl-3-[(5-fluoro-3-indolyl-1Η-indol-2-yl) -phenyl-mercapto]-4-hydroxy-5indole-furan-2-one , (2·{6-murine-2-[(4-controlyl-5·indolyl-2-ylidene-5-phenyl-2,5_digas-σfol-3-yl)- Phenyl-methyl] leads 13-3-yl}-ethyl)-ethylamine, (2-{2·[(4-yl-5-isobutyl-2-isoxyl-2), 5-nitrafloxacin-3-ylphenyl-methyl]-.1313-3-yl}•ethyl)·ethinamine 'N-[2-(2 - {[5-(2 - Cyclohexyl-ethyl)-4-lightyl-2-ylidery-2,5-diaza-σ-fusan-3-yl]-phenyl-methyl}-6·gasyl-1Η-σ -3-yl)-ethyl]-acetamide, Ν-(2-{6-disorganized 2-[(4-glycosyl-2-yloxy-5·phenylethyl-2,5-) -N-nitrogen------------------------------------------------- -5-Sideoxy-3-phenyl-hydroquinone-1 -fine base)-ben

116339.doc 19· 1313683 yl-methyl]·1Η令朵_3_基}_ethyl)_乙乙胺' II (2-{6-fluoro-2-[(2_经基_5_) Side oxyphenyl-cyclopenta-cycloalkenyl)-phenyl-methyl] “" 嗓 基 基 乙基 乙基 ethyl ethyl acetate,

Ν (2 {5-ethyl 2 -[(2_carbyl_5_ pendant oxy small phenyl-cyclopentanyl)-phenyl-methyl μ1 Η, π 基 卜 乙基 ethyl) Ν-(2-{2-[(2-hydroxy-5"-oxyl-3-phenyl-cyclopentyl-nonylenylphenyl-indenyl]-5-methyl--乙乙乙乙胺, 2_{[3_(2_Amino-ethyl)-6-ethyl-1Η-indol-2-yl]-phenyl-fluorenyl}·3·Phase_4·Benzene Base·cyclopenta-2·xanthone or N-(2-{6-chlorohydroxyl j-oxyl_3_phenyl-cyclopenta-diphenyl)-phenyl-methyl]dH-吲哚_ 3-Base}-1,1-dimercapto-ethyl)-acetamide. The compounds of the present invention can be prepared, for example, by the general synthetic procedures described below. General Synthetic Procedures Abbreviation · DMSO: Disulfoxide sulfoxide LDA : Diisopropyl guanamine clock THF: tetrahydro σ saponin I) The compound of formula (1) can be prepared according to the following Scheme 1:

Process 1 HO ?1

III IV V

R R D6339.doc *20- 1313683 A, R, R, R, R2, R3, R4, R5 and R6 are as defined above. The coupling of the oleic acid III, the aldehyde iv and the oxime v to form the oleic acid 1 may be in the solvent (such as 'CH3CN) or an acid (such as carbonic acid, such as formic acid or preferably acetic acid), in the range of 20-100 ° C The reaction is carried out for 1-20 h at a temperature inside (preferably at 70 ° C). • Π)_1) The starting material of the formula ιπ(Α = 0) can be prepared according to the following Scheme 2: - Process 2

OMe

• A + S R R ο

VI R4 and R5 are as defined above. The aldehyde or ketone VI can be in a solvent (e.g., diethyl ether or thf) in the presence of a base (e.g., lithium diisopropyl amide) and at -1 Torr. 〇 to _5〇. Reaction with 3(E)-methoxy-decyl acrylate at a temperature within the range of 〇 (preferably at -80 ° C) (Miyata, Okiko; Schmidt, Richard R.; Angewandte Chemie (1982), Xin 94 (8) ), 65 1-2) to obtain tetronic acid methyl ester ii (a = 〇). The cleavage of the methoxy group in II (A = 0) can be achieved by a strong mineral acid (such as hi, HBr or HCl, preferably HBr) in water and acetic acid and at 2 Torr. 〇 to a temperature in the range of 100 ° C (preferably at 40 ° C) to obtain a special window acid III (A = 0) 〇 II) - ii) Formula III (A = NH or A = N-Ci- The starting material of 6 Hyunji can be based on, for example, Hofheinz, Werner et al, Helvetica Chimica Acta (1977), 60(2), 660-9 or Hilpert, Hans et al. 'US Pat. Appl. Publ. (2005) The following Process 3 is described in US2005119329: 116339.doc 21 1313683 Process 3

Amino acid methyl ester VII can be combined with chlorocarbonyl-ethyl acetate in solvent (eg

HO

In the presence of a test (eg, a sulfonylamine, preferably a triethylamine) and a temperature in the range of up to 6 (in the range of 22 <;t) The reaction is carried out to give propidamine VIII (A = NH or A = NC丨-6 alkyl).

The cyclization of propylenediamine VIII can be carried out in a solvent (e.g., two by a strong base (e.g., sodium pentoxide, potassium butoxide or preferably bis(trimethyl)). Ethyl bond, THF, benzene or preferably toluene) and in the oxime. « _6 〇〇 c within the range of «a degree (preferably at 22 C) to obtain tetramic acid derivative IX (A = NH or A = N-Cw alkyl). The decarboxylation of the dadomiic acid derivative IX can be carried out at 22 ° C to 100 in the presence of a weak acid and a strong acid such as acetic acid and trifluoroacetic acid. (: (preferably 8 (TC) is completed to obtain dadominic acid III (A = NH or A = N-C _6 alkyl).

II)-iii) The starting material of formula III (A = CH2) may be according to Nguyen, Hanh Nho et al, Journal of the American Chemical Society (2003), 125 (39), 11818-11819 or Hamer, Neil K., etc. Man, Tetrahedron Letters (1986), 27(19), 2167-8. II)-iv) The starting materials of formula III can also be prepared according to the following references: 11) Hofheinz, Werner et al., Helvetica Chimica Acta (1977), 60(2), 660-9; 12) Galeotti, Nathalie et al. , Journal of Organic Chemistry (1993), 58(20), 5370-6; 116339.doc -22- 1313683 13) Hilpert, Hans et al, US Pat. Appl. Publ. (2005), US2005119329; 14) Krepski, Larry R. et al., Tetrahedron Letters (1985), 26(8), 981-4; 15) Compain, Philippe et al., Synlett (1994), (11), 943-5; 16) Nguyen, Hanh Nho et al. , Journal of the American Chemical Society (2003), 125(39), 11818-11819; 17) Hamer, Neil K. et al., Tetrahedron Letters (1986), 27(19), 2167-8; 18) Matsuo, Keizo Et al, Chemical & Pharmaceutical Bulletin (1984), 32(9), 3724-9; 19) Mizuno, Hatsuhiko et al, Chemical & Pharmaceutical Bulletin (1975), 23(3), 527-37. III) The starting materials of formula IV are all gambling. IV) The starting materials of formula V are commercially available or can be prepared according to the following references: 1) Ho, Beng T. et al., Journal of Medicinal Chemistry (1971), 4(6); 2) Hasegawa, Masakazu et al. , Heterocycles (1999), 51(12), 2815-2821; 3) Contour-Galcera, Marie-Odile et al., Bioorganic &

Medicinal Chemistry Letters (2005), 5(1 5), 3555-3559; i' c '; 116339.doc -23- 1313683 4) Khalil, Ehab Μ. et al., Journal of Biological Chemistry (1998), 273 (46) ), 30321-30327; 5) Nenajdenko, Valentine G. et al., Tetrahedron (2004), 60(51), 11719-11724; 6) Cheve, Gwenael et al., Medicinal Chemistry Research (2002), 1 1(7) , 361-379 ; 7) Mor, Marco et al, Journal of Medicinal Chemistry (1998), 41 (20), 3831-3844; ^ 8) Heath-Brown, B. et al., Journal of the Chemical

Society, Abstracts (1965), (December), 7165-78; 9) Bastian, Jolie Anne, etc., \¥.0.?乱乱1;.八卩卩1.?131 (2003), WO 2003016307 10) D. Nagarathnam et al., Synthetic Communications (1993) 23 (14), 2011-2017; 20) Hengartner, Urs et al., Journal of Organic Chemistry, (1979), 44(22), 3741-7; Yang, Shyh-Chyun et al., Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1999), 38B(8), 897-904; 22) Tsuchiya, Michihiro et al., International Patent Application, WO 8200032 (1982); 23) Pfister, Jurg R., et al., U.S. Patent Application Serial No. 5,436,264 (1995). As stated above, the compound of formula (I) is the active compound and inhibits chymosin. c: S ) 116339.doc -24- 1313683 "Hai and other compounds thus prevent the activation of angiotensin π, endothelin, TGFb, Ub SCF, collagenase and proteins such as thrombin, FN, Ap〇A1, 2 Degradation. It can therefore be used to treat and/or prevent allergic, inflammatory and/or fibrotic disorders such as allergic H peripheral obstructive disease, severe limb ischemia, vulnerable atherosclerotic plaque, unstable sputum Pain, congestive heart failure, left ventricular hypertrophy, ischemia-reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetes

Intestinal susceptibility, Crohn's disease, atherosclerosis, and/or burns/diabetes ulcers/CLI. Allergies! Health, inflammatory or fibrotic diseases, especially atherosclerotic thrombosis or asthma, are preferred indications for prevention and/or treatment. Accordingly, the invention is also directed to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable excipient. The invention likewise comprises a compound as described above for use as a therapeutically active substance, which is especially useful as a therapeutically active substance for the treatment and/or prevention of allergic, inflammatory and/or fibrotic diseases, in particular for use as a treatment and/or Prevention of allergies, asthma, peripheral arterial occlusion, _ disease, severe limb ischemia, vulnerable atherosclerotic plaque, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemia/reperfusion injury, stroke, myocardial Symptoms, restenosis, rheumatoid sputum, diabetic nephropathy, intestinal irritation, Crohn's disease, atherosclerosis, and/or burns/diabetes/therapeutic active substances in diabetes. The invention also relates to the use of a compound as described above for the preparation of a medicament for the treatment and/or prophylactic treatment of allergic, inflammatory and/or fibrotic diseases, J16339.doc -25·1313683 Particularly for the therapeutic and / or prophylactic treatment of allergies, asthma, peripheral arterial obstructive m limb ischemia, vulnerable atherosclerotic plaque, 猨 -, & - ^ ^ unstable angina, congestion Heart failure, left ventricular hypertrophy, ischemia-reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel disease, Crohn's disease, atherothrombosis Formation and / or burn / ulcer in diabetes / CLI. The drugs comprise a compound as described above. The invention also relates to methods and intermediates for the manufacture of compounds of formula (1) and to methods of making such intermediates. The inhibition of chymosin by the compounds of the invention can be confirmed by assaying the peptide substrate as described below. For chymosin, a substrate containing the 4 amino acid peptide AAPF is selected as a chymotrypsin compound (amber _Ala_Ala_Pr〇_phe_[7_Amino_4_ decyl coumarin], Lockhart BE et al. "Recombinant human mast-cell chymase: an improved procedure for expression in

Pichia pastoris and purification of the highly active enzymQ.''Biotechnol AppI Biochem. May 26, 2004 as a standard publication, the original substrate of BA20040074). A peptide with a purity of 95% was synthesized by Bachem, Bubendorf, Switzerland. A chymosin purified from human skin mast cells was obtained from Calbiochem (Merck Biosciences, San Diego, California, US A). The assay buffer is 0.15 M NaCl, 0.05 M Tris HC1, 0.05% CHAPS (3-[(3-cholestyrylpropyl)-dimethylammonio]-1-propane sulfonate), 0.1 mg/ml heparin (Heparin sodium, Sigma, porcine intestinal mucosa), 〇·〇2 mM AAPF-substrate, 1 nM 116339.doc • 26- 1313683 Doubtase pH 7.4. The assay was performed in a 96-well plate (Packard Optiplate) at a volume of _ ml at room temperature. The chymosin activity is indicated by the initial rate of increase of free 7-amino-4f f-coumarin released from the substrate under layer (10) (excitation/emission). The inhibitory activity of the inhibitory compound was read in a :AAPF-substrate assay buffer at room temperature with chymosin pre-incubation %: clock. The heartbeat value of the active compound of the present invention is then preferably equal to about (1) nM, particularly about (30) to about (1) η Μ β Instance lC50 (by starting with the addition of the specified concentration of ΑΑρρ_substrate). nM) Example 11 13 Example 16 24~~ Example 43 3 Example 63 10 Example 67 5-- Example 72 15 Example 79 1 The compound of the formula U) and/or its medicinal, the salt of the '1^ can be used For example, 'in the form of a pharmaceutical preparation for m ^ 4 intestinal, parenteral or topical killing. It can be, for example, orally (for example, in the form of a lozenge, a J-coated lozenge, a icing dance)

Hard and soft gelatin capsules, solutions, emulsion glands (5) L in the form of Za/Night or suspended liquid), J intestine (for example, in the form of suppositories), parenteral (eg «% -V to 彳 main shot / 谷液或悬Tablets. In the form of ointments, creams or oils. Oral administration is preferred. Preparation of pharmaceutical preparations can be compounded by the formula I, +, i, and the formula I / or its medicinal, A, the salt of the party (depending on the situation | he has a combination of therapeutic value), combined, non-toxic, inert, ☆ U6339.doc -27- 1313683 therapeutic compatibility The solid or -Mm second-night carrier material and, if necessary, the W Le adjuvant are combined to form a herbal-sword-administered form.) Wei Zhikou is not only an inorganic carrier material. Therefore, for example, bacillus, τ I is an organic carrier 'corn starch or its derivative stearic acid or a salt thereof can be used as a tablet, ~, moonstone knife, capsule carrier, material #, agent, sugar coating Pills and hard gelatin. For the soft gelatin, the plant, the cockroach/capsule 5 carrier-like substance is, for example, a nature, macro, #. and liquid menthol (depending on the active ingredient). Suitable carrier materials for the preparation of solutions and sugars which may not require any loading - for example, are water, polysterols, sucrose, invert sugar. For the injection of A, k. ^ ^ 々 a combination of liquid carrier materials such as: Xi Xiang alcohol, glycerin and vegetable oil. Suitable carrier materials for suppositories are, for example, natural or hardened oils, -m feng yue fat and + liquid or liquid multi-read. Suitable carrier materials for topical formulations are glycerin _, semi-synthetic glycerin vinegar, hydrogenated oil, liquid soil 1 state rocky soil, liquid fatty alcohol, leaven, polyethylene glycol and cellulose derivatives. Consider general stabilizers, preservatives, wetting and emulsifying agents, _ degree improvers, flavor improvers, salts for changing osmotic pressure, buffer substances, solvents, colorants, and masking agents and antioxidants. Agent. The dose of the compound of formula (1) may vary within a wide range depending on the disease to be controlled, the age of the patient, and the individual's condition and mode of administration, and of course, the individual needs should be met in each particular case. For adult patients, the daily dose may be considered to be about H_mg, especially about i to post. Depending on the severity of the disease and the precise pharmacokinetic profile, the compounds may be administered in one or several daily dosage units, for example, in sputum to 3 dosage units. 116339.doc -28- 1313683 The pharmaceutical preparation suitably contains about 1.5 mg (preferably Ji 〇〇 mg) of the compound of formula (1). [Embodiment] The following examples are intended to illustrate the invention in more detail. However, the examples are not intended to limit the scope of the invention in any way. General procedure A: Preparation of methyl ester II (A = 〇). A solution of 5.47 g of 3(8)-methoxymethyl acrylate in 4.5 ml of THF at -95C to -l〇〇t Add to a solution of 2 〇ml lDA (2 M, φ in THF) and 130 ml of THF, and continue stirring at the same temperature for 5 min followed by addition of (33 mmol) in 4.5 ml of THF over 2 min. Pre-cool the solution (-78. 持续 and continue stirring for 3 〇 min at -l〇〇t, and stir for 1 h at _78t>c. Pour the cold solution onto 130 ml of ice water and use 6 5 guanidine solution (3 7%) Adjust the pH to 4 and separate the layers. The aqueous layer is extracted twice with di-methane, the organic layer is washed with brine, dried and evaporated. The residue is chromatographed on cerium oxide. Alkane/AcOEt, various ratios) to obtain a special acid 甲 Π Α Α Α Α Α 肇 肇 肇 肇 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特 特(Α = 〇, a mixture of 1 〇 HCl solution (37%) until the reaction is complete. The suspension is filtered and the residue is washed with ice cold water and dried. The layers were washed with brine, dried and evaporated.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ General Procedure C: Preparation of Dadomitoate (Α = ΝΗ or A = N-Cw alkyl). Diethylamine (56 mmol) and gas-based-acetic acid B at C (21 5 116339.doc) -29- 1313683 mmol) was added continuously to a mixture of methyl amino VII (A = NH2* a = alkyl), 18 mmol) in di-methane (60 ml) and stirring overnight. The filtrate was evaporated and the residue was partitioned between EtOAc EtOAc (EtOAc m. Separate to give propylenediamine VIII (A = NH or A = NC 丨 6). At 22 ° C, use bis(tridecyldecane) potassium potassium in THF (3), 9 M, 7 Methyl) A mixture of propionamide VIII (A = NH or A = N-Cu alkyl, 7 mmol) in toluene (12 ml) and stirring for 1-16 h. The suspension was filtered and the residue dried Dadomiic acid Derivative Ιχ (A = nh or A - N-Ci-6 alkyl). The Dadomi acid derivative IX (A = NH or A = NC -6 alkyl, 7 mmol) in acetic acid (40 ml) The mixture in trifluoroacetic acid (4 ml) was heated to reflux for 1 - 5 h. The mixture was evaporated and the residue was chromatographed on silica gel using diethyl ether to afford succinic acid In (A = NH or A = = N-Cw).

Example A Preparation of 4-hydroxymethyl-5-phenyl-5H-furan-2-one A1. Acetophenone was reacted with 3(E)-decyloxy-methyl acrylate using general procedure A' to give Colorless solid racemic 4-methoxy-5-methyl-5-phenyl-5H-anone. MS: 204.1. A2. Separation of racemic _4_methoxy-5-mercapto-5-phenyl-5H-furan-2-one (0.50 g) on Chiralpack AD using n-heptane/ethanol (9:1) (s)-4_Methoxy-5-methyl-5-phenyl-5H-furan-2- _ 116339.doc •30· 1313683 (0.24 g) and a slower dissolving peak (R) _4_methoxy_5_methyl_5_phenyl_5H_furan-2~one (0.24 g). A3. Hydrolysis of (S)_4_methoxy·5•indolyl_5_phenyl_5H_fun-2-one using the general procedure B' to give (8)·4_base_5_ as a colorless solid Methylphenyl group _ kk 2-m 0 MS: 190.2 ([M]+) 〇[a] 365nm: -420.4° (1%, CHC13) 〇A4. Using general procedure B, make (R)_4_A Hydroxy_5_methyl·5_phenyl-5H-furan-2-one is hydrolyzed to give (R)_4_hydroxy-5-methyl-5-phenyl-5H-brown-2_ as a colorless solid ketone. Ms: ι9〇·2 ([M] + ). [a] 365 nm: +441.5. (1〇/〇, CHC13).

Example B Preparation of racemic-5-(2-cyclohexyl·ethylhydroxy-5H-furan-2-one) B1. Using a general procedure A' to make a ring of propylene (Stratakis, Manolis et al., Journal of 〇 Rganic chemistry (2002), 67(25), 8758-8763) is reacted with 3(E)-methoxy-methyl acrylate to give racemic-5-(2-cyclohexyl-ethyl) as a colorless solid. _4-decyloxy-5H-furan-2-_. MS: 225.2 ([M+H] + ). B2. Using General Procedure B to give racemic-5-(2-cyclohexyl-ethyl)- 4-Methoxy-5H-furan-2-one is hydrolyzed to give a racemic _5-(2-cyclohexyl-ethyl)-4-yl-5-5-f-f-but-2-one as a brown solid. MS: 211.1 ([M+H]+).</RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> </RTI> <RTIgt; Preparation of -hydroxy-7a-methyi-5,6,7,7a-tetrahydro-pyrrolizin-3-one) Using the general procedure C, the thio-2-indolylpyrrolidine-2-carboxylate was converted. </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

Example D (R)_5_Benzyl_4-hydroxymethyl-I,5-dihydro-pyrrole-2-one was prepared using the general procedure C to give (R)_2-amino-2-methyl 3-Phenyl-propionic acid methyl ester was converted to the title compound obtained as a white solid. MS: 204.1 ([m+h]+) 〇

Example E (R)-4-Hydroxy-5-isopropyl-5-methyl 4,5-dihydro-pyrrole-2-one was prepared using the general procedure C' to give (R)_2-amino-2, Conversion of 3-dimethyl-butyrate decanoate to the title compound obtained as a white solid. MS: 156.3 ([M+H]+).

Example F (1^)-4_Phenyl-5-fluorenyl-5-phenyl-1,5-dihydro-0-pyrid-2-one was prepared using General Procedure C to give (R)-2- The amine 2-phenyl-propionic acid methyl ester was converted to the title compound [Lit 19] obtained as a colorless oil. MS: 190.3 ([M+H] + ). [α] 3 6 5 n m · +360.9 (c = 1%, CHC13). General procedure D: coupling of ruthenium hydride, aldehyde IV and hydrazine V. A solution of oleic acid (1 mmol), aldehyde (1.3 mmol) and hydrazine (1 mmol) in acetic acid (2 ml) at 70 C Mix for 16 h. The suspension was filtered and the residue was washed with MeOH /EtOAc (2 EtOAc). If no precipitation occurred, the solution was purified by preparative HPLC (RP-18, CH3CN/H20, gradient). Example 1 N-(2_{2-[(4-Hydroxy-5-isopropyl-2-yloxy-2,5-dihydro-1Η-» 比略_3 116339.doc -32· 1313683 base) -phenyl-methyl]-1H-indole-3-yl}-ethyl)-acetamide

Using the general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-one (literature (hereinafter referred to as !^.11)) and benzofural and &gt; 1- [2-(111-Indol-3-yl)-ethyl]-acetamide was reacted to give the title compound as a pale yellow solid. MS: 432.5 ([M+H] + ) ° Example 2 N-(2-{2-[(3-fluoro-phenyl)-(4-hydroxy-5-isopropyl-2-yloxy) 2,5-Dihydro-1Η-»Byr-3-yl)-methyl]-1H-indol-3-yl}-ethyl)-acetamide

Using the general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-one (Lit. 11) with 3-fluoro-benzofural and hydrazine-[2-(1Η) -Indol-3-yl)-ethyl]-acetamide is reacted to give the title compound as a yellow solid. MS: 450.1 ([M+H] + ). Example 3]\-(2-{2-[(4-Fluoro-phenyl)-(4-hydroxy-5-isopropyl-2-yloxy-2,5-dihydro-1H-pyrrole- 3-yl)-methyl]-1H-indol-3-yl}-ethyl)-acetamide 116339.doc -33- 1313683

Using the general procedure C' to make 4-carbyl-5-isopropyl-1,5-di-mouse-D ratio B-2.0 (Lit. 11) with 4-fluoro-benzaldehyde and hydrazine-[2 -(1Η-Indol-3-yl)-ethyl]-acetamide is reacted to give the title compound as a yellow solid. MS: 450.3 ([M+H] + ).

Example 4]^-(2-{2-[(3,5-Difluoro-phenyl)-(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H) -pyrrol-3-yl)-methyl]-1H-indol-3-yl}-ethyl)-acetamide

Using the general procedure C' to make 4-carbyl-5-isopropyl-1,5-diaza-D ratio ·-2- 酉 (1^.11) with 3,5-difluoro-benzene Formaldehyde and 1^-[2-(111-indol-3-yl)-ethyl]-acetamide are reacted to give the title compound as a yellow solid. MS: 468.0 ([M+H]+). Example 5 2-{2-[(4-Hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-phenyl-methyl]-1H acetate -吲哚-3-yl}-ethyl ester 116339.doc -34 - 1313683

Using the general procedure C' to give 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrolidone (Lit·11) with benzaldehyde and 2-(ih-indol-3-yl) - ethanol reaction to give the title compound as an orange foam. MS: 433.3 ([M+H]+). Example 6 4-Carboxy-3-{[3·(2-hydroxy-ethyl)-ih-indol-2-yl]-phenyl-methyl}_5-isopropyl-I,5-dihydro-比Bilo-2-one

Mixing 2-{2-[(4-carbyl-5-isopropyl-2-yloxy-2,5-dihydro-1Η-pyrrol-3-yl)-phenylate at 22 C A solution of -methyl]-1Η-indol-3-yl}-ethyl ester (40 mg) and LiOH (8.5 mg) in MeOH (0.5 ml). The residue was partitioned between 〇 1 N HCl aqueous solution and AcOEt and the organic layer was dried and evaporated. The residue was chromatographed on EtOAc (EtOAc) eluting eluting MS: 391.1 ([M+H]+). Example 7 1^-(2-{2-[(4-Hydroxy-5-isopropyl-2-yloxy-2,5-dihydro-111-pyrrol-3-yl)-phenyl-methyl ]-1H-indol-3-yl}-ethyl)-benzimidamide 116339.doc -35- 1313683

Using the procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Ut·U) and stupid formaldehyde and hydrazine-[2-(1Η-吲哚-3- The title compound is obtained by the reaction of phenyl hydrazide to give the title compound as a gray solid. MS: 494_3 ([M+H] + ). Example 8 Ν·(2-{2-丨(4-hydroxyisopropyl_2_sideoxy-2,5•dihydro-1H_pyrrole_3_yl)-phenyl-methyl]-1Η-吲Indole-3-yl}-ethyl)-3,5-bis-trifluoromethyl-benzamide

8·1· Ν·[2·(1Η-,哚-3-yl)-ethyl]_3,5-bis-trifluorodecyl-benzoguanamine was prepared at 22&lt;&gt;(:, will &gt ;^{3(1.74 1111) and 3,5-bis-trifluoromethyl-benzoquinone (1.24 ml) were added to 2-(1Η-indol-3-yl)-ethylamine (1.0 g) The solution in CH2C12 was stirred for a further 16 h at 22 ° C. The mixture was washed with aq. EtOAc (H.sub.2) 8.2. Using General Procedure C, 4-hydroxy-5-isopropyl.is-dihydro-pyrrole-2-one (Lit. 11) with benzaldehyde and hydrazine-[2-(1Η-吲哚_3) _Ketylethyl 3 5_116339.doc -36- 1313683 bis-trifluoromethyl-benzamide to give 1 (2-{2-[(4-carbyl-5-isopropyl) as a red solid Keto-2-mercapto-2,5-diox-1H-Dtb-tris-yl)-phenyl-indenyl-1H-indol-3-yl}-ethyl)-3,5- Bis-trifluoromethyl-benzamide. MS: 630.2 ([M+H] + ). Example 9 Cyan-2-acid acid (2-{2-[(4-amino-5-isopropyl) -2-Sideoxy-2,5-diaza-1Η_ &quot;birol-3-yl)-phenyl-indenyl]-1Η-indol-3-yl}-ethyl)-decylamine

Using the general procedure C' to make 4-fluoro-5-isopropyl-1,5-diaza-α ratio slightly 2-reward (Lit. 11) with benzaldehyde and naphthalene-2-sulfonic acid [2-( 1Η-Indol-3-yl)-ethyl]-nonylamine (Lit. 1) was reacted to give the title compound as an orange solid. MS: 580.3 ([M+H]+). Example 10 3 - [(5-Gasyl-3-methyl-1Η-β-consyl-β-l-yl)-phenyl-methyl]-4-transyl-5-isopropyl-1,5 ·Two gas -ntLing · - 2 -嗣

Using the general procedure C' to make 4-light-based-5-isopropyl-1,5-di-mouse-D-pyr-2-酉(Lit. 11) with benzaldehyde and 5-fluoro-3-methyl -1H-indole to give the title compound as a yellow solid. MS: 3 77.1 ([Μ-ΗΓ). 116339.doc -37- 1313683 Example 11 3-[(5-Alkyl-3-methyl-1Η-β-bendene-2-yl)-phenyl-indenyl]-4-yl--5-iso Propyl-1-methyl-1,5-dihydro-pyrrol-2-one

4-hydroxy-5-isopropyl-1-indolyl-1,5-dihydro-pyrrol-2-one (Lit. 12) with benzaldehyde and 5-fluoro-3-indol using general procedure C The reaction is carried out to give the title compound as a yellow solid. MS: 391.3 ([M-Η]·). Example 12 4-Hydroxy-5-isopropyl-3-[(3-indolyl-1H-indol-2-yl)-phenyl-indenyl]-1,5-dihydro-&quot;Bilo- 2-ketone

Using the general procedure C, 4-(yl)-5-isopropyl-1,5-diaza-D-pyr-2-anthracene (Lit. 11) with benzaldehyde and 3-methyl-1H-indole Reaction to give the title compound as a yellow solid. MS: 361.0 ([M+H] + ). Example 13

3-[(5-fluoro-3-isopropyl-1H-indol-2-yl)-phenyl-indenyl]-4-hydroxy-5-isopropyl-1,5-diaza-° ratio洛-2 - Brewing I 116339.doc -38- 1313683

13.1. A 5-fluoro-3-isopropyl-1H-portlet was prepared as a light brown oil similar to Lit. 10, MS: 177.0 ([M]+). 13.2. Using General Procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) with benzofurfural and 5-fluoro-3-isopropyl -1H-oxime reaction to give 3-[(5-fluoro-3-isopropyl-1H-indol-2-yl)-phenyl-indenyl]-4-yl--- 5-isopropyl-1,5-diaza-Dtbn each -2-indole. MS: 405.2 ([M-Η]·). Example 14 N-(2-{2-[(4-carbyl-2-ylidene-2,5-diaza-nf-amyl-3-yl)-phenyl-methyl]-1H-indole -3-yl}-ethyl)-acetamide

4-Hydroxy-5H-furan-2-one is reacted with benzofural and N-[2-(1 fluorenyl-3-yl)-ethyl]-acetamide using General Procedure C to give The title compound of the orange foam. MS: 391.1 ([Μ+Η] + ). Example 15 Ν-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl)-phenyl-methyl]-1Η -吲哚-3-yl}•ethyl)·acetamide 116339.doc -39- 1313683

Using general procedure C, 5-benzyl-3-hydroxyl-5-furan-2-one (Lit. 13) with benzaldehyde and N-[2-(1 Η-indol-3-yl)-B The reaction is carried out to give the title compound as a white solid. MS: 481.0 ([Μ+Η]+). Example 16 Ν~(2·{2-[(5-benzoinyl_4_hydroxy_2_sideoxy-2,5-dihydro-furan-3-ylphenylindolyl)·6_Fluorine Base-1Η-indol-3-yl}-ethyl)-acetamide

16·1_ Ν-[2-(6-Fluoro-Iιη-indol-3-yl)-ethyl]-acetamide added acetic anhydride (〇·43 ml) to 2·(6-fluoro- 1Η-Indol-3-yl)-ethylamine (0.88 g) and NEt3 (2 27 ^1) in a solution of Cil2Cl2 (8 ml) and stirring at 22 C for 1 h. The mixture was washed with a 1 N aqueous HCl solution and the organic layer was dried and evaporated. The residue was chromatographed on EtOAc (EtOAc) elute MS: 219.1 ([M-Η]·). 16.2. Using General Procedure C, 5_Benzyl_4_hydroxy_5H_furan-2-one (Lit. 13) and benzaldehyde and N_[2_(6•fluoroyl_iH-fluorenyl)_ Ethyl]acetamide is reacted to give a white solid meaning (2_{2_[(5_benzyl_4_hydroxy_2-o-oxy-2,5-dihydrofuran_3_yl)) Phenyl_methyl]_6_fluoroyl_ΐΗι 116339.doc -40- 1313683 Orido-3-yl}-ethyl)-acetic acid amine. ]VIS: 497.4 ([M-Η]-). Example 17 N-(2-{2-[(5-Butmethyl-4_hydroxy_2. sideoxy-2,5-dihydro-furan-3-yl)_phenyl-methyl]-5 - gas base_1H-吲哚_3_ base}_ethyl)_acetamide

5-Benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) with benzoic acid and N-[2-(5-alkyl-1H-indole-3-) using the general procedure C' The reaction was carried out to give the title compound as a white solid. MS: 513.1 ([M-Η]·). Examples 18 and 19: 5-Benzyl_3-{[6-fluoroyl_3_(2-hydroxy-ethyl)_1H[_吲哚_2_yl]-phenyl-methyl}-4- ke-SH·furan-2-ketone and acetic acid 2_{2-[(5-benzyl-4-hydroxy-2-one-oxy-2,S-dihydro-furan-3-yl)-phenyl- Methyl]_6_fluoroyl-3-phenyl bromide

5-Benzyl-4-hydroxy-5-furan-2-one (Lit. 13) and benzoquinone and 2-(6-fluoro-1H-indol-3-yl) were prepared using the general procedure C' - Ethanol (Lit. 3) reaction The mixture was isolated by HPLC to give the title compound, titled &lt;RTI ID=0.0&gt;&gt; MS: 456.3. The second fraction contains the second title compound in orange. MS: 498.1 ([M-Η]·). Example 20 Ν-(2-{2-[1-(5-benzoinyl_4_hydroxy_2_ oxo-2,5-diaza-bist-3-yl)-2-methyl- Propyl]-1H-indole-3-yl}-ethyl)-acetamide

Using the general procedure C' to make 5-benzyl-3-hydrox-5H-furan-2·one (Lit. 13) with 2-mercapto-c-age and]^_[2_(111_1^丨〇^3_ The title compound was obtained as a yellow solid. Ms: 445 i ([m_h]·). Example 21 N (2 {2-[1-(5-Benzyl_4_hydroxy-2-yloxy-2,5-dihydro-furan-yl)-3-indenyl-butyl]_1H_吲哚_3 base}•ethyl)·acetamide

Using the procedure C, 5-phenylhydrazin-4-yl-5HH2-one (Li-decyl T acid and N_[2-(1H_0) 11-3-yl)-ethyl]-acetic acid should be To obtain the compound of the formula [X], the compound of the formula. MS: 459.1 ([Μ-ΗΉ. Example 22; 116339.doc -42-1313683 N case 2 phenylmethyl _4, phenyl_2_ side oxygen Base-π dihydrogen henyl)-pentyl]-mM-3-yl}•ethyl)·ethnamine

Make 5&quot; stupid methyl-4-hydroxy_5H-°fol-2-one (Lit·

The reaction was carried out using the general procedure C-yl)-ethyl]-acetamide to give MS: 459.3 ([M-Η],).

13) The title compound with valeraldehyde and hydrazine-[2-(1Η-1% _3 to white solid. Example 23 N-(2-{2-[l-(5-Benzylmethyl+hydroxy_2_ side) Oxy 2,5-dihydro- acetofuryl)-2-phenyl-ethyl]·1 Η, _3 乙基 ethyl) _ acetamide

Using the general theory of C, make 5-benzyl _4_ _ _ Η 咬 咬 _2 嗣 嗣 U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U The title compound was obtained as a white solid. MS: 493 〇 . Example 24 ({2 [1 (5-benzoinyl_4_hydroxy_2. oxo-2,5-diazaindolyl phenyl)-propyl]·1ΗΚ3· kibethyl)-B Guanamine 116339.doc •43 · 1313683

Using a general bud-forming bed p-order C' to make 5-methyl-4_hydroxy_5H_furan-2-ketone (Ut. 13) with phenyl-propionic acid and Ν·[2-(1Η令朵_ The title compound is obtained as a dark solid. MS: 507.2 ([M-Η]·). Example 25 N (2 {2-[(5-Benzylmethylidene-based oxy-2,5-dihydro-fusin_3_yl)-(p-phenylphenylmethyl)-phenylethyl)-acetamide

Using general procedure C, 5-phenylhydrazino-4-hydroxy-5H-furan-2-one (Lit. 13) with 2-fluoro-benzaldehyde and hydrazine-[2-(1Η-吲哚-3- The reaction was carried out to give the title compound as a white solid. MS: 497.3 ([M-Η]·). Example 26 3·{[3-(2-Amino-ethyl)·6-fluoroindol-2-yl]-phenyl-methyl}-5-benzyl-4-hydroxy-5Η-furan 2-ketone; salt formed with acetic acid

116339.doc -44 - 1313683 Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) with benzofural and 2-(6-fluoro-1H- The indole-3-yl)-ethylamine reaction gave the title compound as a light red foam. MS: 45 7.1 ([M+H]+). Example 27 2-·(2-{2-[(5_Benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl)-phenyl-fluorenyl]-1H -Indol-3-yl}-ethyl)-N-methyl-ethylamine

Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) with benzofural and hydrazine-[2-(1Η-吲哚-3-yl)-B The reaction was carried out to give the title compound as a pale yellow solid. MS: 493.3 ([M-Η]·) ° Example 28 1\-(2-{2-[(5-Benzenyl-4-hydroxy-2-oxo-2,5-dihydro-furan- 3-yl)-phenyl-methyl]-5-fluoro-1H-indol-3-yl}-ethyl)-acetamide

Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) with benzaldehyde and N-[2-(5-fluoro-1H-. Reaction of 3-yl)-ethyl]-acetamide (Lit. 5) gave the title compound as a pale yellow solid. MS: 116339.doc -45 - 1313683 497.4 ([MH]') ° Example 29 N-(2-{2-[(5-Benzyl-4-hydroxy-2-yloxy-2,5-di) Hydrofuran-3-yl)-phenyl-methyl]-1-methyl-1Η-indol-3-yl}-ethyl)-acetamide

29.1. N-[2-(l-Methyl-1Η-indol-3-yl)-ethyl]-acetamide is obtained by deuteration from 2-(dimeryl-1Η) as described in Example 16.1. -Indol-3-yl)-ethylamine was prepared to give a pale green oil, MS: 217.4 ([Μ+Η]+). 29.2. Using general procedure C, 5-phenylmercapto-4-hydroxy-5-furan-2-one (Lit. 13) with benzaldehyde and N-[2-(l-fluorenyl-ex--indole- Reaction of 3-yl)-ethyl]-acetamide to give a red solid (2_{2-[(5-benzoinyl-4-hydroxy-2-oxo-2,5-dihydro-)吱 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Ms: 493.3 ([M-Η]". Example 30 5·Benzyl-3·[(5-fluorobased_3_methyl_1H_吲哚_2_yl)_phenyl_methyl b 4_ Mercapyl-5H-*fufen-2-one

Using general procedure C, 13) with benzaldehyde and 5_ to react with methyl-4-bromo-5H-benzo-2-one (Lit. gas-3-methyl-1H-indole to give colorless 116339.doc • 46- 1313683 The title compound as a solid. MS: 426.1 ([MH]-). Example 31 N-(2-{6-carbyl-2-[(4-]-yl-2-yloxy- 5-phenyl-2,5-diazepine-3-3-yl)-phenyl-indenyl-1H-indol-3-ylethyl)-acetamide

Using the general procedure C, 4-hydroxy-5-phenyl-5H-furan-2-one (Lit. 14) with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl) The reaction of -ethyl]-acetamide (Example 1 8.1.) gave the title compound as a pale brown solid. MS: 485.0 ([M+H] + ). Example 32 3-{[3-(2-Amino-ethyl)-6-ethyl-1H-indol-2-yl]-phenyl-methyl}-4-hydroxy-5-phenyl-5H -furan-2-ketone

4-hydroxy-5-phenyl-5H-furan-2-one (Lit. 14) with benzofural and 2-(6-ethyl-1H-called indole-3-yl) using General Procedure C -ethylamine (Lit. 8) was reacted to give the title compound as a white solid. MS: 453.3 ([M+H] + ). Example 33 N-(2-{6-Gayl-2-[(4-carbyl-5-methyl-2-oxo-5-phenyl-2,5--116339.doc-47 - 1313683 Hydrogen-furan-3-yl)-phenyl-methyl]-1H-indol-3-ylethyl)-acetamide

Using General Procedure C, 4-hydroxy-5-methyl-5-phenyl-5H-furan-2-indole (Example A2) with benzaldehyde and N-[2-(6-fluoro-1H-indole) The indole-3-yl)-ethyl]-acetamide (Example 18.1) was obtained to give the title compound as a pale brown solid. MS: 499.5 ([M+H]+). Example 34 1^-(2-{2-[(4-Pyano-5-isobutyl-2-oxo-2,5-dihydro-°f〇^|-3-yl)-phenyl) -曱基]-1H-0 bow -3- -3--3-yl}-ethyl)-acetamide

4-Phenyl-5-isobutyl-5H-fofan-2-one (Lit. 14) with benzaldehyde and hydrazine-[2-(1Η-吲哚-3-yl) using general procedure C -ethyl]-acetamide to give the title compound as a white solid. MS: 441.1 ([M+H] + ). Example 35 2-{2-[(4-Hydroxy-5-isobutyl-2-oxo-2,5-dihydro-furan-3-yl)-phenyl-methyl]-1H-indole哚-3-yl}-ethyl ester 116339.doc -48 - 1313683

4-Hydroxy-5-isobutyl-5H-furan-2-one (Lit. 14) was reacted with benzaldehyde and 2-(1沁吲哚-3-yl)-ethanol using General Procedure C to give The title compound of the orange solid. MS: 448·1 ([M+H] + ). Example 36

N-(2-{2-[(4-Hydroxy-2-oxo-1-oxa-spiro[4.5]indol-3-yl-3-yl)-phenyl-indenyl]-1H-indole Indole-3-yl}-ethyl)-acetamide

Using general procedure C, 4-hydroxy-1-oxa-spiro[4.5]indole-3-en-2-one (Lit. 15) with benzaldehyde and hydrazine-[2-(1Η-吲哚-3- The reaction was carried out to give the title compound as a white solid. MS: 459.1 ([M+H] + ). Example 37 N-(2_{2-[(5-Cyclohexylmethyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl)-phenyl-methyl]-6 -fluoro-1H-indol-3-yl}-ethyl)-acetamide

116339.doc •49- 1313683 Using General Procedure C, 5-cyclohexyldecyl-4-hydroxy-5H-furan-2-one (Lit. 13) with benzofural and N-[2-(6-fluoro) Reaction of the group-1H-indol-3-yl)-ethyl]-acetamide (Example 1 8.1.) gave the title compound as a pale red solid. MS: 503_0 ([M-Η]·). Example 38 N-[2-(2-{[5-(2-Cyclohexyl-ethyl)-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl]- Phenyl-methyl}-6-alkyl-1Η-β 引-3-yl)-ethyl ethene

Using general procedure C, 5-(2-cyclohexyl-ethyl)-4-hydroxy-5-furan-2-one (Example B2) with benzaldehyde and N-[2-(6-fluoro-1H- The indole-3-yl)-ethyl]-acetamide (Example 1 8.1 ·) was obtained to give the title compound as a pale green solid. MS: 517.2 ([Μ-ΗΠ. Example 39 N-(2-{6-fluoro-2-[(4-hydroxy-2-yloxy-5-phenethyl-2,5-dihydro^)喃-3-yl)-phenyl-methyl]-1H-indol-3-yl}-ethyl)-acetamide

Using General Procedure C, 4-hydroxy-5-phenethyl-5H-furan-2-one (Lit. 13) with benzofural and N-[2-(6-fluoro-1H-indole-3) -Based-ethyl]-acetamide 116339.doc -50-1313683 (Example 18_1) was obtained to give the title compound as a pale red solid. Ms: 511.1 ([M-Η]·). Example 40 N-丨2-(6-Fluoro-2-{丨4-hydroxy-2-oxo-5-(3-styl-propyl)_2,5-dihydro-indole 1*South- 3-amino]-phenyl-methyl}-1Η-β 丨 -3-3 -yl)-ethyl]·acetamide

Using the general procedure C, 4-hydroxy-5-(3-phenyl-propyl)-5 quinone-2-furan-2-one (Lit. 13) was combined with benzofuraldehyde and hydrazine-[2-(6-fluoro-l-? - 吲哚_3_yl)-ethyl]-acetamide (Example 18.1.) was reacted to give the title compound as a pale red solid. MS: 525.2 ([Μ-ΗΓ). Example 41 Ν-(2-{2·[(2-Hydroxyl-oxyl-cycloalkenyl)-phenyl-methyl]_1H_ 0-indol-3-yl}-ethyl)-acetamidine amine

Using the general procedure C, 3_hydroxy-cyclopent-2-enone (Lit·16) with benzofural and hydrazine-[2-(1Η-吲哚-3-yl)-ethyl]-acetamide Reaction to give the title compound as a pink solid. MS: 387.4 (|; Μ _ ΗΠ. Example 42 116339.doc • 51 · I313683 N-(2-{2-[(2-hydroxy-5-oxooxy-3-phenyl-cyclopentyl 1-alkenyl)) -phenyl-methyl]-1H-indol-3-ylethyl)-acetamide

Using general procedure C, 3-hydroxy-4-indolyl-cyclopent-2-enone (Lit. 17) with benzoic acid and hydrazine-[2-(1Η-indol-3-yl)-ethyl] - acetamide to give the title compound as a pink solid. MS: 465.0 ([M+H]+). Example 43 N-(2-{6-Fluoro-2-[(2-hydroxy-5-oxaoxy-3-phenyl-cyclopentenyl)-phenyl-methyl]-1H-indole_ 3_基}•ethyl)_acetamide

Using a general private sequence C, 3_hydroxy-4-phenylene-cyclopentenone (Ut. 17) and benzoate and NC (6i-based-1H-.indol-3-yl)ethyl]- The acetamide (Example 18.1.) was reacted to give the title compound as a pink solid. mS: 483·5 ([M+H] + ). Example 44 Ν-(2-{2·[(2-Phenyl-oxyl-3_phenyl-cycloindole small dilute oxime-pyridyl-2-yl-methyl)_11^引嘴-3-yl} -Ethyl)_Ethylamine 116339.doc -52· 1313683 Using the general procedure c: 'Methyl 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) with pyridine-2-carbaldehyde And N_[2-(1H-吲哚·3·yl)-ethyl]-acetamide to give the title compound as a white solid. MS: 466.3 ([M+H]+). (2-{2-[(2-hydroxy-s_o-oxy-3-phenyl)cyclopentanyl)-pyridyl_3_yl-indenyl]-1Η_»丨哚丨哚基乙)) The amine is used in the general procedure C to give 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit·17) to &lt;3-biting&gt;3-carboxylic acid and hydrazine-[2-(1Η_吲哚_3) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ · 5-sidedoxy_3_phenyl-cyclopentenyl)·(1Η•咪峻_4_yl)-methyl]-1Η “丨哚丨哚|基卜ethyl)acetamide using the general procedure C, /N=r\ hnA 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) with 3Η-味哇-4- decanoic acid and Ν吖2_〇Η_吲哚_3 •base The title compound was obtained as a light brown solid. MS: 455.0 ([M+H] + ). Example 47 N-(2-{2-丨(2-hydroxyl) -5-Sideoxy-3-phenyl-cyclopent-1-enyl)-(1Η-imidazol-2-yl)-indenyl]-1Η-indol-3-yl}•ethyl)-B Guanamine

Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) with 1H-imidazole-2-furaldehyde and hydrazine-[2-(1Η-吲哚-3- The reaction was carried out to give the title compound as a pale brown solid. MS: 455.0 ([M+H] + ). Example 48 N-(2-{5-Ethyl-2-[(2-carbyl-5-oxo-3-phenyl-cycloindole-1 -ytyl)-phenyl-methyl]-1H -吲哚-3-yl}-ethyl)-acetamide

Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) with benzofural and N-[2-(5-ethyl-1H-indole-3- The reaction was carried out to give the title compound as an orange solid. MS: 493.4 ([M+H] + ). Example 49 116339.doc -54- 1313683 2_{[3-(2-Amino-ethylmethyl-1H[_吲哚_2_ylbuphenyl_methylbu 3_hydroxy-4-phenyl-cyclo) Pentam-2-one

Using General Procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) with benzofural and 2-(5-ethyl '1H-indol-3-yl)-B The amine is reacted to give the title compound as an orange solid. MS: 437.1 ([M+H]+). Example 50 2-·(2-{2-[(2-hydroxyloxy_3_phenylcyclopentenyl)-phenyl-indenyl]-5-methyl-1Η-吲哚_3_yl Buethyl)-acetamide

3-hydroxy-4-phenyl-cyclopent-2-enone (Lit·17) was combined with phenylfurfural and N-[2-(5-methyl-1H-indole-3-) using the general procedure C The reaction was carried out to give the title compound as an orange solid. MS: 479.0 ([M+H]+). Example 51 2·{[3-(2-Amino-ethyl)-6-ethyl-1H-indol-2-yl]-phenyl-methyl}-3-hydroxy-4-phenyl-cyclo Pen-2-enone 116339.doc • 55· 1313683

- General &amp; C' to make 3_hydroxy-4-phenyl-cyclopent-2-enone (7) with *carboxylic acid and 2-(6-ethyl) tenth _3_yl) ethylamine (6) t. 8 Reaction to give the title compound as a tan solid. MS: 451.0 ([M+H]+). Example 52

N (2-ethyl 2-_2-[(2_-yl- 5-oxyl-3)-phenylcyclophosphazene) phenyl group] methyl]L _3· kibethyl) acetamide

52_1, N-[2_(6-ethyl-1H•吲哚_) was prepared from 2-(6-ethyl-m_吲哚_3_yl)-ethylamine (Lit·8) as described in Example 16.1. 3_yl)-ethyl]-acetamide. 52.2. Using General Procedure C, 3_hydroxy-4-phenyl-cyclopenta-2-ene oxime (Lit. 17) with benzofural and N-[2-(6-ethyl-1H-oxime) -3-yl)·ethyl]-acetamidine is reacted to give N-(2-{6-ethyl-2-[(2-carbyl. 5-oxo-3-benzene) as a pale brown solid. Base-cyclopenta-1-yl)-phenyl-methyl]_ih_dH3-yl}. Ethyl)-acetamide. MS: 493.1 ([M+H] + ). Example 53 2-{[3-(2-Amino-2-methyl-propyl)-6-yl-1H-indol-2-yl]-phenyl-methyl}-3-yl-- 4-phenylcyclopentan-2-one

116339.doc -56 - S 1313683

Using the general procedure C, 3-hydroxy-4-phenylene-cyclopent-2-enone (Lit. π) and benzoic acid and 2-(6-chloro-1H_吲哚_3_ylindole) : mercapto-ethylamine (similar to the preparation of Lit. 9) was reacted to give the title compound as a pale yellow solid. MS: 485.4 ([M+H]+) 〇 54

N-(2-{6-Gasyl-2·[(2-hydroxy-5-oxooxy-3-phenyl-cyclopentenyl)phenyl-methyl]-1Η-indol-3-yl Dimethyl-ethyl)-acetamide

3_Base)-1,1-Dimethyl-ethylamine (prepared to the preparation of Lit 9) was prepared to give a saponin of the chloroform-1H-indole-3-yldidecyl-ethyl]-acetamide. 54'2' using the general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit·17) with benzofural and N-[2_(6_气基_1H_吲哚_3_基)_,, dimethyl-ethyl]-acetamide reacted to give N_(2_丨6_气基_2-[(2-hydroxy_5_ side oxygen) as a pale yellow solid Base_3·phenyl-cyclopentanyl-phenyl-methyl]_ιΗ_ 引木3-基}_ι,ι_ monomethyl-ethyl)-acetamide.ms: ([M+H]+) Example 55 116339.doc -57- 1313683 H_(2-{6-Gasyl_2-[(2-hydroxy-5_sideoxy_3_phenyl-cyclopentenyl)phenyl-methyl] -5-methoxy_1H_0 哚 _3_ kibethyl) acetamide

The benzene group was reacted with N-[2-(6. chloro methoxy methoxy hydrazinyl hydrazinyl)-ethyl]-ethylamine to give the title compound as a pale red solid. MS: 529.3 ([M+H]+). Example 56 N-(2_{2-[(2_Phenyloxy-3-phenyl)cyclopentenyl)-phenylmethyl]-6-methoxyl_1Hh3_ylethyl)_B Guanamine

Using the general procedure C, 3_hydroxy-4-phenyl-cyclopent-2-enone (ut· with benzoquinone and N-[2-(6-methoxy_1H) _3_yl) _Ethyl]•Ethylamine (10). 7) Reaction to give the title compound as a light red solid. Ms: 495 5 ([M+H] + ). Example 57 2-·(2-{2-[(2-carbyl-s-sideoxy-3-indolylcyclopentyl)phenylmethyl]-5-decyloxy·1Η-μ_3_&amp; Ethylamine 116339.doc -58- 1313683

Using the general procedure C, 3_hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) and the present formic acid 'and N-[2-(5' 曱 丨 丨 _ _ _ 3 -3 The reaction was carried out to give the title compound as a light red solid. MS: 495.4 ([M+H] + ). Example 58 3-U6-Fluoro-3-(2-hydroxy-ethyl)_1H-indole-2-yl]-phenyl-methyl}-4-carbyl-5-isopropyl-hydrazine, 5 _二氮_D比洛_2·嗣

Using the general procedure D, racemic 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) with benzofural and 2-(6-fluoro- Reaction of 1H-indol-3-yl)-ethanol gave the title compound as a pale yellow solid. MS: 409.1 ([M+H]+). Example 59 2-丨(5-Fluoro-3-methyl·1H_吲哚_2_yl)-styl-methyl] 4-hydroxy-7amethyl-5,6,7,7a-tetrahydro _ϋ比呻_3_ ketone

II6339.doc -59· 1313683 Using the general procedure D, rac-hydroxy-7a-mercapto-5,6,7,7a-tetrahydro-pyridin-3-one (Example C) with benzofural Reaction with 5-fluoro-3-indolyl-lH-indole to give the title compound as a red solid. MS: 391.1 ([M+H]+). Example 60 3-[(5-Gasyl-3-methyl)-phenyl-methyl]-4-yl-5,5-dimethyl-I,5·diar-pyridin-2-one

Using the general procedure D, the racemic _4_hydroxy-5,5-dimercapto-1,5-dihydro-&quot;birol-2-one (Lit. 18) with benzofuraldehyde and 5-fluoro The benzyl-3-mercapto-1 oxime-oxime reaction gave the title compound as a yellow solid. MS: 3 65.1 ([M+H]+). Example 61 (R)-5-Benzyl-3-[(5-fluoro-3-methyl-1H-indol-2-yl)-phenyl-methyl]hydroxy_5-methyl-1 ,5-dihydro-pyrrole_2-one

Using the general procedure D' to make (R)_5_benzoinyl_4_hydroxy_5_methyl_丨,5_dihydro-13 to 嘻-2-嗣 (Example D) with benzaldehyde and 5-fluoro _3_Mercapto-1H_, oxime to give the title compound as a yellow solid. MS: 441.1 ([M + H] + ). Example 62 (R)_3-[(S-Fluoro-3-methyl-1H_吲哚_2_yl)-phenyl-methyl]_4_hydroxy_ 116339.doc -60- 1313683 5_isopropyl Base_5_mercapto-1,5-dihydro-dehydrazol-2-one

Using General Procedure D, (R)-4-hydroxy-5-isopropyl-5-methyl-1,5-dihydro-indol-2-one (Example E) with benzaldehyde and 5-fluoro -3-indolyl-1H-indole was reacted to give the title compound as a pale yellow solid. MS: 393.1 ([M+H] + ). Example 63 N-{2-[((R)_4-hydroxymethyl_2_sideoxy_5_phenyl-2,5-dihydro-1H_0-l-l-)-phenyl-methyl]·6 _methyl_1H•吲哚_3_ylmethylethylamine

Ό3 · 1 · 6-mercapto-1H-called 丨 κ 3 - 曱 月 at 22 ° C 'Add hydrazine hydrochloride (0.46 g) and sodium acetate (0.54 g) to 6-methyl-1H - hydrazine-3-carbaldehyde (0.96 g, Lit. 20) in ethanol (30 ml) solution and the mixture was stirred for 3 h. The mixture was evaporated and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ MS: 175.3 ([M+H] + ). 63.2. C-(6-Methyl-lH-n-indol-3-yl)-methylamine Sodium borohydride (3.04 g) was added in portions to 6-methyl-1 Η- at 22 C '. Tobacco -3- aldehyde oxime (0.66 g) and NiCl2 6H2 〇 (〇 97 g) are in a mixture of sterol (6 〇 ml) 116339.doc • 61 · 1313683. The suspension was filtered and the filtrate was evaporated. The residue was partitioned between EtOAc (EtOAc) (EtOAc) 63.3. N-(6-Methyl-1H-°Induce D--3-ylmethyl)_Acetamine Add acetic anhydride (0.14 m) and pyridine (0.13 ml) to c_(6•methyl ) _ methylamine (〇 · 24 g) in dichlorohydrazine (4 in solution = and continued to stir at 22t for 20 min. Wash the mixture with HCl aqueous solution (1N), will

The organic layer was dried <RTI ID=0.0></RTI> to EtOAc (EtOAc) MS: 203.1 ([Μ+Η]+). 63.4. Using General Procedure D, make (8)·4· benzylmethyl-5 phenyla dihydrom_ (Example F) with benzoic acid and hydrazinylmethyl _ιη令多-&gt; ylmethyl)-acetamidine The amine is reacted to give the title compound as a white solid. MS: 478.4 ([M-Η]·). Example 64

(R)-4-carbyl_5-methyl-3-[(3-methyl5-phenyl-1,5-dihydropyrrol-2-yl-1H-吲哚_2_yl)_ Phenyl-methyl b

Using the general procedure D, let (R)_4_hydroxyλ i. &amp; base _5~ decyl-5-phenyl-1,5-dihydro. arro-2-one (prepared according to Lit. 11 and also see Llt·19) with benzaldehyde and 3, ketone- 1H-吲哚 reaction to get yellow

The title compound of the bar/package bed. 1S 116339.doc -62· 1313683 409.2 ([M+H] + ). Example 65 (R)-3-[(3,5-.monomethyl-1Η-η5|β-l-yl)-phenyl-methyl- 4-yl-5-indenyl-5-benzene ke-I,5-dihydro-pyrrole-2-one

Using the general procedure D' to give (R)-4-hydroxy-5-methyl-5-phenyl 4,5-dihydro-pyrrol-2-one (prepared according to Lit. 11, see also Lit. 19) with benzene Formaldehyde and 3,5-dimethyl-1H-indole (Lit. 21) were reacted to give the title compound as a yellow foam. MS: 423.3 ([M+H]+). Example 66 (R)-3-[(3,6-Dimethyl_1H_吲哚_2_yl)-phenyl-methyl-b-hydroxyl- 5 fluorenyl~5-phenyl-I,5· Dihydro-»比略_2_ketone

Using the general prion D, let (R)-4-transyl-5-methyl-5-phenyl-i,5-dihydro-π ratio each, 2~_ (prepared according to Lit. 11, see also Lit. I9) is reacted with benzaldehyde and 3,6-~methyl-1H-indole (Lit. 22) to give the title compound as a yellow foam. MS: 423.3 ([M+H]+). Lean 67 [(5-fluoro-3-methyl-indolyl)-phenyl-methyl]_4_yl-yl-ll6339.d〇c-63- 1313683 5-decyl-5-phenyl- 1,5-dihydro-pyrrol-2-one

Using the general procedure D' to give (R)-4 -transyl-5-methyl-5-phenyl-1,5-di-r-pyrrol-2-one (prepared according to Lit. 11, see also Lit. 19) Reaction with phenylfurfural and 5-fluoro-3-methyl-1H-indole to give the title compound as a pale yellow foam. MS: 425.4 ([M-H]·). Example 68 5-Benzyl-3-[(5-fluoro-3-indolyl-1H-indol-2-yl)-thiophen-2-yl-methyl]-4-hydroxy-5H-furan- 2-ketone

Using the general procedure D, racemic-5-phenylhydrazin-4-hydroxy-5H-furan-2-one (Lit. 13) with thiophene-2-furaldehyde and 5-fluoro-3-indolyl- 1H-indole reaction gave the title compound as a red solid. MS: 434.3 ([M+H] + ). Example 69 5-Benzyl-3-[(5-carbyl-3-methyl-1Η-Π弓丨-2·yl)-隹-phen-3-yl-methyl]-4-hydroxy-5H -furan-2-one

116339.doc -64- I313683 Using the general procedure D, the racemic-5-phenylhydrazin-4-hydroxy-5H-furan-2-((Lit. 13) with thiophene-3-furfural and 5-fluoro The benzyl-3-methyl-1H-indole is reacted to give the title compound as a colorless solid. MS: 434.3 ([M+H] + ). Example 70 Ν·(2-{6-Gasyl_2_[(4_hydroxy_5_methyl_2_sideoxy_5_phenyl-2,5-dynefufen-3-yl)- Phenyl-fluorenyl]-1 Η-β丨丨0-3-yl}-1,1-dimethyl-ethylethenamine

Μ·1·Chloro-1Η-indol-3-yl)-1,1-dimethylethyl}ethylamine 2-(6-chloro-1Η-吲 as described in Example 63.3哚-3-based)·! ,! Dimethyl-ethylamine (prepared analogous to Lit. 9) was deuterated to give the title compound as a brown semi-solid. Not 7 0.2. Weitian > Wind using general procedure D to make racemic 4-hydroxy-5-mercapto_5 1 its southern ~2-ketone (prepared according to Example A3) with benzaldehyde and hydrazine _[2- (6_ gas base _ 1 Η - mouth quotation, u ' soil 〃 -3 -yl)-1,1 - dimethyl-ethyl]-ethramine reaction to obtain a brown solid § * A ' 暇Title compound. MS: 543.3 ([M+H] + ). Example 71

Nfc(2_{S-carbyl-2-[(4-hydroxy-5-methyl-2-oxo-5-phenyl_2,5-dis- 3,yl)-phenylindolyl] Indole-3-yl}-1,1-dimethyl-ethyl)-ethylamine 116339.doc -65- 1313683

71.1. N-[2-(5-Chloro-1H-indol-3-yl)-1,1-diindolyl-ethyl]-acetamidine 2-(5) as described in Example 63.3. -Chloro-1H-indol-3-yl)-1,1-dimercapto-ethylamine (Lit. 23) was purified to give the title compound as a colorless solid. MS: 263.1 ([M-Η]·). 71.2. Using General Procedure D, racemic-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-one (prepared according to Example A3) with benzofurfural and N-[2-( 5-Hydroxy-1H-indol-3-yl)-1,1-dimercapto-ethyl]-acetamide was reacted to give the title compound as a pale brown solid. MS: 543.3 ([M+H] + ). Example 72 N-{2-[((R)-4-Pentyl-5-mercapto-2-yloxy-5-phenyl-2,5-diaza-β夫-3-yl)- Phenyl-methyl]-6-mercapto-1Η-indol-3-ylindenyl}-acetamide

Using general procedure D, (R)-4-hydroxy-5-mercapto-5-phenyl-1,5-dihydro-pyrrole-2-one (Example A4) with benzaldehyde and N-(6-A The reaction was carried out to give the title compound as a yellow solid. MS: 479.4 ([Μ-ΗΠ. Example 73 N-{2_[((S)-4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydro-furan- 3-yl)-phenyl-indenyl]-6-methyl-1H-indol-3-ylmethyl}-acetamide 116339.doc -66· 1313683

Using the general procedure D' to give (S)-4 -transyl-5-mercapto-5-phenyl-1,5-di-r-pyrrol-2-one (Example A3) with benzaldehyde and N-( Reaction of 6-methyl-1H-indol-3-ylindenyl)-acetamide (from Example 63.3) gave the title compound as a yellow solid. MS: 479.4 ([M-Η]·). Example 74

(R)-4-hydroxy-5-methyl-3-[(3-methyl-1H-indol-2-yl)-phenyl-methyl]-5-phenyl-5H-furan-2- ketone

Using the general procedure D' to give (R)-4-transyl-5-methyl-5-phenyl-1,5-di-r-butan-2-one (Example A4) with benzaldehyde and 3-oxime The reaction is carried out to give the title compound as a yellow solid. MS: 408.4 ([Μ-ΗΓ). Example 75 (R)-3-[(3,5-Dimethyl-1H-indol-2-yl)-phenyl-methyl]-4-hydroxy-5-methyl-5-phenyl-5H -furan-2-one

Using the general procedure D' to give (R)-4-|^i--5-mercapto-5-phenyl-1,5-di-r-butan-2-one (Example A4) with benzofurfural and 3,5-Dimethyl-1H-. Reaction (Lit. 21) 116339.doc -67- 1313683 to give the title compound as a light brown solid. MS: 422.5 ([ΜΗ]·). Example 76 (R)-3-[(3,6-Dimethyl-1Η-11 引-2 -yl)-phenyl-methyl]-4-yl-5-methyl-5-phenyl -5 Η - β夫味-2 - 明

Using the general procedure D' to give (尺)-4-carbyl-5-mercapto-5-phenyl-1,5-di-r-pyrrol-2-one (Example A4) with benzaldehyde and 3,6 - Dimercapto-1H-. Reaction (Lit. 22) gave the title compound as a light brown solid. MS: 422.4 ([ΜΗ]·). Example 77 (R)-3-[(5-Fluoro-3-methyl-1Η-indol-2-yl)-phenyl-methyl]-4-hydroxy-5-methyl-5-phenyl -5H-furan-2-one

Using ~~ General Procedure D' to give (R)-4-yl-pyridin-5-mercapto-5-phenyl-1,5-diaza-α-pyrol-2-one (Example Α4) with benzofural and 5-fluoro-3-methyl-1oxime-oxime to give the title compound as a yellow solid. MS: 426.1 ([M-Η]·). Example 78 3-Hydroxy-2-[(3-methyl-1H-indol-2-yl)-phenyl-methyl]-4-phenyl-cyclo 116339.doc -68- 1313683 pent-2-back嗣

Using the general procedure D, the racemic _ 3 -trans--4-phenyl-cyclopent-2-enenone (Lit. 17) is reacted with benzaldehyde and 3-methyl-1H-indole to give a red color. The title compound of the solid. MS: 394.1 ([M+H] + ).

Example 79 2-[(5-Fluoro-3-methyl-1H-indol-2-yl)-phenyl-methyl]-3-hydroxy-4-phenyl-cyclopentene-2-infant

Reaction of racemic _3_hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) with benzaldehyde and 5-fluoro-__methyl-1H•吲哚 using general procedure D The title compound was obtained as a magenta solid. Ms: 412.〇 ([M+Hp.

Example A A film-coated tablet containing the following ingredients can be prepared in a conventional manner: 10.0 mg per tablet. 2 〇 0. 〇 2 23.5 mg 43.5 mg 60.0 mg 70.0 mg 12.5 mg l5. 〇 12.5 mg 17.0 mg 1.5 mg 4.5 mg 120.0 Mg 350.0 mg Ingredient core: Compound of formula (I) Microcrystalline cellulose, water-containing lactose, polyethylene, Billow, K30, glycolic acid, sodium starch, stearic acid (core weight) 116339.doc -69- 1313683 Membrane: 3.5 mg 7.0 mg 0.8 mg 1·3 mg 1-6 mg 〇*8 mg 2.6 mg 0.8 mg 1.6 mg 1.6 mg , team day cellulose hydroxypropyl methylcellulose PEG 6000 talc iron oxide ( Yellow) A solution of titanium dioxide (10) in water causes the mixture to form granules: ================================================ Μ core. The cores are coated with an aqueous solution/suspension of the above film coat.

EXAMPLE B Capsules containing the following ingredients can be prepared in a conventional manner: Compound of formula (I), lactose corn starch, talc powder, sifted and mixed the components. Example C The injection solution can have the following composition of formula (I). Alcohol 400 acetic acid injection solution with water 25.0 mg 150.0 mg 20.0 mg 5.0 mg per capsule and 3.0 mg 150.0 mg in size 2 capsules, pH 5.0 plus 1.0 ml Dissolve the active ingredient in polyethylene glycol 400 and water for injection (partial) of the 2 compounds. The pH was adjusted to _ 5 . By adding the remaining amount of water, the volume is § weeks to 1 · 〇 ml. The solution was filtered, filled into vials r as appropriate and sterilized.

Example D A soft gelatin capsule containing the following ingredients can be made in a conventional manner: 116339.doc -70- 1313683 Capsule content Compound 5 of formula (I), 0 mg yellow wax 8.0 mg hydrogenated soybean oil 8.0 mg partially hydrogenated vegetable oil 34.0 mg large Soybean oil 110.0 mg Capsule content 165.0 mg Gelatin capsule gelatin 75.0 mg Glycerin 85% 32.0 mg d-sorbitol (Karion) 83 8.0 mg (dry matter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in the warm-melted other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are processed according to the usual procedure.

Example E A sachet containing the following ingredients can be made in a conventional manner: Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg Carboxymethylcellulose sodium salt 14.0 mg Polyethylene °Pilokenone K 30 10.0 mg Magnesium stearate 10.0 mg Flavoring additive 1.0 mg The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and mixed with polyvinylpyrrolidone in water. It becomes granular. The granules are mixed with magnesium stearate and a flavoring additive and placed in a sachet. 116339.doc -71 -

Claims (1)

^44192 Patent Application Replacement of the Gradient Range (March 98) J A Patent Application Range: 1' A compound of formula (1), Wherein: 1 A is _CH2-, -Ο- or -NR'-, wherein R' is hydrogen or c a 6-alkyl φ group, or R' and R4 form a c2_5 stretching base; R is hydrogen, halogen, nitro , cyano, amine, cK6 alkyl, heteroalkyl, Cw cycloalkyl, c2.6 alkenyl, c2.6 alkynyl, hydroxy, cN6 alkoxy, •NRIRn, -(匸0.6alkyl) -NR'R&quot;, wherein R' and R&quot; are independently selected from the group consisting of hydrogen, Ci-6 alkyl, heteroalkyl, methionyl, C]·6 alkylcarbonyl, optionally substituted c3 7 cycloalkyl Carboxolyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heterocyclylcarbonyl, C6·6 sulfonyl, optionally substituted c3 7 a cycloalkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted heteroarylsulfonyl group, and optionally a substituted heterocyclic sapphire group, or -(C〇_6 Extrusion group - 0RI 'where R is hydrogen, CN6 alkyl, heteroalkyl, methantyl or Cw alkylcarbonyl; 116339-980327.doc 1313683 R2, R2' and R2' are independently hydrogen, halogen, cyanide Base, nitro, amine group, single or two Ci- 6 Hyun-substituted amino group, alkyl group, Cz_6 dilute group, C2-6 alkynyl group, heteroalkyl group, hydroxyl group or ci-6 alkoxy group; R3 is hydrogen, halogen, cyano, nitro, amine, amine substituted by mono or diCl 6 alkyl, Ck alkyl, C2·6, c26, heterogeneous, technical, C1 6 alkoxy, optionally substituted C3.7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted C3 - 7 cycloalkyl-C1-6 alkyl, optionally substituted aryl-C -6 groups, optionally substituted heteroaryl-Ci-6 leukoxyl or optionally substituted heterocyclic group _Ci 6 alkyl; R4 is nitrogen, halogen, cyano, nitro, amine, amine substituted by mono or di q alkyl, C, · 6 alkyl, C 2 · alkenyl, alkynyl, hetero The base, hydroxyl, and Ck alkoxy groups are taken as appropriate Substituted C3-7 cycloalkyl, optionally substituted aryl, substituted heteroaryl, optionally substituted, heterocyclically substituted C3·7 cycloalkyl-Ci_6 alkyl, in view ring a group, optionally, a heteroaryl-C1-6 alkyl group or an optionally substituted heterocyclic group -C1_6 alkyl; 6疋R5 is hydrogen or cN6 alkyl; or R4 and R5, as the case may be. The carbon atom to which it is attached - constitutes optionally substituted C3-7 cycloalkyl ring or optionally substituted heterocyclyl ring; 1I6339-980327.doc 1313683 R is hydrogen or cK6 alkyl; and its medicinal An acceptable salt; wherein: the term &quot;heteroalkyl&quot; means a Cl 6 alkane substituted by one or more substituents independently selected from the group consisting of nitro, hydroxy, halo, cyano, C 6 alkoxy, indenyl, Ck6 alkyl, carboxy, CM alkylthio!, ·6 Cl-6, sulfinyl, 6 alkylsulfonyl, amine and mono- or di- a group of alkyl-substituted amine groups; The term &quot;aryl&quot; means phenyl or naphthyl; the term &quot;heteroaryl&quot; means a monocyclic or bicyclic group having 5 to 12 ring atoms having at least one aromatic ring containing 1, 2 or 3 ring atoms selected from N, oxime and S, the remaining ring atoms are c, provided that the point of attachment of the heteroaryl group is attached to the aromatic ring; the term &quot;heterocyclyl&quot; means 3 to 8 ring atoms of the (four) family of monocyclic or bicyclic groups, their towels! Or 2 ring atoms are heteroatoms selected from N, 〇 〇 to 2 integers, and the remaining ring atoms are c; (eight is the term "optionally substituted aryl,", as the case may be substituted "Heteroaryl", "optionally substituted heterocyclic group" and "optionally substituted Cw cycloalkyl" mean, respectively, one or more independently selected from halo, nitro, cyano, amine, respectively. a aryl group substituted with a substituent of a group consisting of a group consisting of a group consisting of a group of a group consisting of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group , a heteroaryl group, a heterocyclic group, and a C3 7 cycloalkyl group. 2. The compound of claim 1 wherein R is a C1·6 yard group, optionally substituted with an aryl group of 116339-980327.doc 1313683, optionally substituted a heteroaryl group, optionally substituted aryl Cl. 6 alkyl or, optionally substituted, heteroaryl Cl-6 alkyl. 3. A compound of the formula 3 and 2, wherein r3 is匸]6 alkyl; phenyl C -6 alkyl phenyl substituted by 1 to 3 fluorine atoms, or heteroaryl substituted by m 1 to 3 fluorine atoms Is a monocyclic aryl group having 5 or 6 ring atoms, which contains - a ring nitrogen atom or 1 ring sulfur atom. 4. A compound according to any one of claims 1 to 2, wherein R, phenyl. 5) The compound of any one of 2, wherein ... is Cl, an alkyl group, (C0.6 alkylene) _NR, R&quot;, wherein R, and r&quot; are independently selected from 氲Ci·6 alkane Alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl & |, fluorene substituted arylsulfonyl and substituted arylsulfonyl a group of base groups; or _(Cg.6alkylene)_ 〇R', wherein R' is hydrogen or a C0 alkylcarbonyl group. A compound according to any one of items 1 to 2, wherein r1 is a 6 alkane — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — And a group of aryl groups; or _(C2 decyl) _ 〇R, wherein R' is hydrogen or acetamyl. 7. A compound according to any one of items 1 to 2, wherein Rl is 2-aminoethyl, 2-ethylamidoethyl, 2-ethylamino group _2,2-Diethylethyl, methyl, isopropyl or 2-hydroxyethyl. 8. The compound of any one of claims 1 to 2, wherein R 2 , r 2 , and r 2 are independently hydrogen. Having a compound of any one of claims 1 to 2, wherein R2, R2' and R2' are two of the compounds of the formula 1 to 2, wherein the two are Hydrogen, and the other is hydrogen, a hydroxyl, a CM alkyl or a Ci0 alkoxy. The compound according to any one of claims 1 to 2, wherein two of R2, R2, and R2" are hydrogen, and the other is hydrogen, chloro, fluoro, thiol, ethyl or methyl A compound according to any one of claims 1 to 2, wherein R2, R2' and r2, two of which are hydrogen' and the other is at the 5 or 6 position of the anthracene ring and Is a group consisting of #hydrogen, chloro, fluoro, thiol and ethyl. 12. A compound according to any one of claims 1 to 2, wherein R6 is hydrogen. A compound according to any one, wherein: R is hydrogen, Ci-6 alkyl, optionally substituted c3-7 cycloalkyl, optionally substituted aryl, optionally substituted c37 cycloalkyl Ci6 alkyl or, as appropriate, Substituted aryl c] 6 alkyl, and r5 is hydrogen or cN6 alkyl; or R and 11 together with the carbon atom to which it is attached, constitutes a c37 substituted cycloalkyl ring as desired. The compound of any one of claims 1 to 2, wherein R2 is hydrogen, or R5 is hydrogen. 16. The compound R' as claimed in any one of claims 2 to 2 is hydrogen or Ci.6 base. The compound according to any one of claims 1 to 2 wherein A is _ch2- &lt; wherein A is _ch2- R4 wherein A is -NR', wherein R is 氲 or methyl, and R4 is different And a compound of any one of claims 1 to 2, wherein eight is _〇_. A compound according to any one of 2, wherein a is _〇_, R4 is hydrogen, phenyl, C 1-6 alkyl, optionally substituted Cw cycloalkylcl6 alkyl or optionally substituted aryl c a 6 alkyl group and R5 is hydrogen or a Ci_6 alkyl group; or R and R together with the carbon atom to which it is attached constitute an optionally substituted C3 7 cycloalkyl ring. 2〇·If any of claims 1 to 2 A compound of the formula wherein VIII is _〇_, R4 is phenyl, phenylhydrazine, isobutyl, 2-cyclohexylethyl or phenethyl and the caliper 5 is hydrogen&gt; or fluorenyl. a compound of 1 which is: 3·[(5-fluoro-3·methyl_1H-吲哚_2-yl)·phenyl-methyl]_4_hydroxy·% isopropyl-1,5- Dihydropyrrol-2-one, 3-[(5-fluoro-3-methyl-1H-吲哚_2-yl)-phenyl-methyl]-4_hydroxy- _ -1-methyl-1,5-dihydro-pyrrole-2-one, 4-hydroxy-5-isopropyl-3-[(3-methyl·1H_吲哚_2_yl)phenyl -Methyl]_ 1,5-dihydro-. Ratio p _ 2 -keto, ^ 3-[(5-fluoroyl_3_isopropyl_ιΗ_吲哚_2_yl)_phenyl- Methyl 4-hydroxy- 5-isopropyl-1,5-dihydropyr/2-one, Ν-(2-{2-[(5-phenylhydrazin-4-hydroxy_2_ side oxygen) Base 2,5-dihydro-furan-3-ylphenyl-methyl]_6_fluoroyl_1Η_吲哚_3-yl}-ethyl)-acetamide, 5-methyl- 3- {[6-Fluoro-3-(2-trans)-ethyl)_ιη_, 0_2_2-yl]-styl-methyl}-4-pyrene-2-one, 3-{ [3 -(2-Amino-ethyl)-6-fluoro-ih-indole-2-yl]-phenyl-indolyl 5-benzoinyl-4-hydroxy-5H-furan-2-one; Salt formed from acetic acid, 116339-980327.doc 1313683 5-Benzyl-3-[(5-fluoro-3-methyl-1H-indol-2-yl)-phenyl-methyl]_ 4- Benzyl-5H-c-butan-2-one, (2-{6-fluoro-2-[(4-hydroxy-5-mercapto-2-yloxy-5-phenyl-2,5-di) Hydrofuran-3-yl)-phenyl-indenyl]-indole_3_yldiethyl)-acetamide, (2-{2-[(4-hydroxy-5-isobutyl-2- side) Oxy-2,5-dihydro-furan-3-yl)-phenyl-indenyl]-oxime -3-yl}-ethyl)-acetamide, N-[2-(2-{[5-(2-cyclohexyl-ethyl)-4)hydroxy-2-epoxy-2,5_2 Hydrogen_furan-3-yl]-phenyl-methyl}_6•fluoroyl_1H_吲哚_3_yl)-ethyl]•acetamidine, N-(2-{6-fluoro-2 -[(4-hydroxy-2-oxo-5-phenethyl-2,5-dihydro-furan-3-yl)-phenyl-indenyl]_1H_吲哚_3_ylethyl)_ Acetamide, N-(2-{2-[(2-hydroxy-5_yloxy_3_phenyl-cyclopentyl-nonyl)phenyl]methyl]-1H-indole-3- }}_ethyl)_acetamidine, N-(2-{6-fluoro-2-[(2-hydroxy-5- oxo_3_phenyl-cyclopentyl-fluorenyl-alkenyl)_ Phenyl-methyl]-1H-indol-3-yl}-ethyl)·acetamidine, N-(2-{5-ethyl-2-[(2-hydroxy-5-sideoxy)- 3-phenyl-cyclopentamethoxy-alkenyl)-phenyl-methyl]-1Η-indol-3-yl}-ethyl)-acetamidamine, Ν-(2-{2-[(2 -hydroxy-5-oxooxy-3-phenyl-cyclopentyl-1-alkenyl)-phenyl-indenyl]-5-methyl-1Η-吲哚_3-yl}-ethyl)-B Indoleamine, 2-{[3-(2-amino-ethyl)_6-ethyl·1Η-.哚_2_yl]-phenyl-methyl}_ 3-hydroxy-4-phenyl-cyclopent-2-enone or oxime-(2-{6-carbyl-2-[(2-hydroxyl) -5-Sideoxy-3-phenyl-cyclopentyl-indole-alkenyl-methyl]-1Η-indole-3-ylpyridinium-dimethyl-ethyl)-acetamide. A pharmaceutical composition comprising a compound of 116339-980327.doc 1313683 and a pharmaceutically acceptable excipient according to any one of claims 1 to 21. 23, as claimed in claims 1 to 2 A compound for use as a therapeutically active substance. 24. Use of a compound according to any one of claims 1 to 21 for the preparation of a medicament for the treatment of allergies, asthma, peripheral arterial occlusive disease, severe Limb ischemia, vulnerable atherosclerotic plaque, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemia-reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, Intestinal irritability, Crohn's disease (disease), atherothrombotic thrombosis or ulceration/diabetes ulcers/(: sputum drugs. 116339-980327.doc